Introduction

Exploration of Targeted Anti-tumor Therapy

2692-3114

Open Exploration

100253

10.37349/etat.2021.00053

Review

A novel strategy for treating cancer: understanding the role of Ca²⁺ signaling from nociceptive TRP channels in regulating cancer progression

https://orcid.org/0000-0003-1034-4977

Hsu

Wen-Li

¹ ²

https://orcid.org/0000-0002-9674-069X

Noda

Mami

https://orcid.org/0000-0003-2831-6421

Yoshioka

Tohru

² ⁴

https://orcid.org/0000-0002-1877-6566

Ito

Etsuro

⁴ ⁵ ⁶ ^* Pan

Zui

1Department of Dermatology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80145, Taiwan 2Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan 3Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan 4Graduate Institute of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan 5Waseda Research Institute for Science and Engineering, Waseda University, Tokyo 162-8480, Japan 6Department of Biology, Waseda University, Tokyo 162-8480, Japan The University of Texas at Arlington, USA

*Correspondence: Etsuro Ito, Waseda Research Institute for Science and Engineering, Waseda University, Tokyo 162-8480, Japan. eito@waseda.jp

2021

31 10 2021

2 401 415 04 06 2021 12 08 2021

2021

This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Cancer is an aging-associated disease and caused by genomic instability that is driven by the accumulation of mutations and epimutations in the aging process. Although Ca²⁺ signaling, reactive oxygen species (ROS) accumulation, DNA damage response (DDR) and senescence inflammation response (SIR) are processed during genomic instability, the underlying mechanism for the cause of genomic instability and cancer development is still poorly understood and needs to be investigated. Nociceptive transient receptor potential (TRP) channels, which firstly respond to environmental stimuli, such as microbes, chemicals or physical injuries, potentiate regulation of the aging process by Ca²⁺ signaling. In this review, the authors provide an explanation of the dual role of nociceptive TRP channels in regulating cancer progression, initiating cancer progression by aging-induced genomic instability, and promoting malignancy by epigenetic regulation. Thus, therapeutically targeting nociceptive TRP channels seems to be a novel strategy for treating cancers.

Aging nociceptive transient receptor potential channel cancer progression

Introduction

Cancer is a genomic disease. Increased rates of cancer in an aging population are an integral component of aging associated diseases [1]. Because genomic instability is caused by the accumulation of mutations and epimutations in the aging process, it contributes significantly to activation of oncogenes and dysfunction in tumor suppressor genes, which are involved in cancer development [2]. Genomic instability derives from DNA damage response (DDR), and the p53 family proteins drive the DNA repair system to recover errors caused by genomic instability in order to maintain homeostasis of normal tissue [3]. Once there is a blockage of the balance between genomic instability and the DNA repair system, DDR results in p53 family proteins dysfunction which promotes cancer progression [4].

Genomic instability is the most important condition to induce cancer development, but it may trigger the key process in initiating cancer progression before activation of oncogenes and dysfunction in tumor suppressor genes. Based on the mitochondrial free radical theory of aging, excessive increase in intracellular reactive oxygen species (ROS) levels induces genomic instability and would lead to cellular dysfunctions and aging [5]. Intracellular ROS accumulation can be stimulated by mitochondria Ca²⁺ overload [6]. Therefore, Ca²⁺ signaling plays an important role in determining intracellular ROS accumulation, DDR, and genomic instability following initiation of cancer progression.

Ca²⁺ signaling is also a crucial regulator of pathways in promoting cancer progression with oncogenic activation [7]. The contribution of Ca²⁺ signaling to cancer cell growth, metastasis and chemotherapy resistance has been extensively investigated [8, 9], including regulation by epigenetic mechanisms to induce malignancy [10]. The therapeutic targeting of Ca²⁺ signaling provides a novel approach for treating cancer. Recently, nociceptive transient receptor potential (TRP) channels, which belong to a special group of TRP channels, have been involved in the nociceptive pathway and include members of the TRP ankyrin (TRPA), and TRP canonical (TRPC), TRP mucolipin (TRPM) and TRP vanilloid (TRPV) subfamilies that potentiate regulation of the aging process and tumorigenesis by Ca²⁺ signaling [11–15]. This is different from the classical function of nociceptive TRP channels in excitable cells (neurons, muscle cells and some endocrine cells) that causes an influx of ions through the cell membrane to induce a depolarization of the cell which in turn triggers action potentials [16]. Most cancer cells are classified into non-excitable cells, and overexpressed nociceptive TRP channels in cancer cells are thus unusual [17]. However, multiple roles of Ca²⁺ signaling from nociceptive TRP channels in cancer development have been independently reported. In this review, we discuss and summarize the possible mechanisms that indicate Ca²⁺ signaling from nociceptive TRP channels modulates cancer progression.

Ca2+ signaling from nociceptive TRP channels potentiates initiation of cancer progression Nociceptive TRP channels respond to environmental stimuli and cause the aging process

Nociceptive TRP channels are predominantly expressed by distinct subsets of sensory neurons of the peripheral nervous system [18], which cause an initial response to environmental stimuli, especially microbes, chemicals or physical injuries. Although numbers of TRP channels are identified by their characteristics and functions, several TRP channels are characterized by nociceptive TRP channels, including TRPA1, TRPC1/C3/C5/C6/C7, TRPM2/M3/M8 and TRPV1/V2/V3/V4, which are involved in the nociceptive pathway [19]. Interestingly, these nociceptive TRP channels in non-excitable or excitable cells potentially initiate the aging process due to excess Ca²⁺ signaling from active nociceptive TRP channels upon continual environmental stimuli [11–15]. Environmental stimuli, such as bacterial endotoxins, oncovirus, di-(2-ethylhexyl)-phthalate (DEHP), particulate matters (PMs) or ultraviolet radiation have responding nociceptive TRP channels. The responding TRP channels of environmental stimuli was illustrated in Table 1. Some environmental stimuli (e.g., PMs) can directly activate nociceptive TRP channels [20], but others activate nociceptive TRP channels through G protein-coupled receptors (GPCR) [21]. The GPCR-TRP axis mediates sensation and inflammation responses to environmental stimuli; for instance, after irradiation by ultraviolet B (UVB), the activation of nociceptive TRP channels (e.g., TRPC7) induces response to UVB-induced skin damage through the GPCR-phospholipase C (PLC)-diacylglycerol (DAG) signaling [13]. When environmental stimuli activates the responding TRP channels, increased Ca²⁺ influx contributes to oxidative stress [22]. Mitochondria Ca²⁺ overload induces intracellular ROS accumulation and DDR, which triggers the senescence inflammation response (SIR) and senescence-associated secretory phenotype (SASP) activation, leading to genomic instability and cancer progression [23].

Table 1.

Nociceptive TRP channels respond to environmental stimuli

Environmental stimuli	Category		Nociceptive TRP channel	Reference
Microbes	Gram-negative bacteria: bacterial endotoxins		TRPA1, TRPM3, TRPM8, TRPV1	[81]
	Oncovirus	EBV	TRPA1	[82]
		HBV	TRPC6	[83]
		HPV	TRPV4	[84]
Chemicals	Mustard oil, formalin		TRPA1	[85]
	Menthol, icilin		TRPM8
	DEHP		TRPV1	[86]
	Particulate matter		TRPA1, TRPC6, TRPM2, TRPV1, TRPV4	[20]
Physical injuries	Mechanical gating		TRPA1, TRPC1, TRPC3, TRPC6, TRPM8	[87]
	UVA		TRPA1	[88]
	UVB		TRPC7	[13]

EBV: Epstein-Barr virus; HBV: hepatitis B virus; HPV: human papilloma virus; UVA: ultraviolet A

Ca2+-activated K+ channels potentially trigger the cell cycle in initiating tumorigenesis

Excess Ca²⁺ signaling from active nociceptive TRP channels upon continuous environmental stimuli may lead to cancer progression that is due to the change of intracellular proton dynamics [24–26]. It is still unclear how Ca²⁺ signaling controls intracellular proton dynamics to initiate cancer progression and to promote tumorigenesis. Proton signaling, especially Ca²⁺ signaling, influences changes in water properties and water content in the cytoplasm that occur along with the cell cycle [27]. According to the novel theory of cancer research, the water structure between primary cells and cancer cells is completely different; the water structure in the primary cell (cell cycle arrest) is bound (like an iceberg) and molecules cannot move freely [24]. Interestingly, in cancer cells (cell cycle activation), water is free and molecules can move around easily. Proton diffusion determines if the cell physiology is faster than protein interaction [27]. Indeed, many proteins perform their functions by also being dependent on proton dynamics. In primary cells, Ca²⁺ signaling from active nociceptive TRP channels potentiates activation of Ca²⁺-activated K⁺ channels to reduce the intracellular K⁺ concentration, which releases cell proliferation by releasing the cell cycle and the intracellular water structure (Figure 1), and the free molecules, such as ions, proteins or nucleotides can move easily to maintain cell survival. This could be key to the role of Ca²⁺ in initiating tumorigenesis, because Ca²⁺ signaling from active nociceptive TRP channels requires polarization of the cell membrane and thus consequently activity of K⁺ channels, which are decisive for cell proliferation [28], similar to fertilization in triggering the development [29]. The fast proton diffusion method confirmed that fertilization induced the formation of free water from bound water [30].

Figure 1.

Environmental stimuli-activated nociceptive TRP channels disturb the balance between cell death and survival by high-magnitude Ca²⁺ entry. Upon the release of cell cycle arrest by initiating the aging process, the fate of cells is determined: death or survival. The repair system, such as p53 protein family is involved in this determination. When genomic instability cannot be repaired due to dysfunction of the repair system, the release of cell cycle arrest in senescent cells results in tumorigenesis, because senescent cells don’t progress to cell death. Senescent cells could initiate the cell cycle through Ca²⁺-activated K⁺ channels which are activated by nociceptive TRP channels, and stabilize the released-cell cycle with activation of oncogenes and dysfunction of tumor suppressor genes. On the other hand, in the aging process, nearly all cells face ROS released from mitochondria and DDR and SIR, and if the p53 protein family is activated, eventually contribute to cell death. Environmental stimuli-activated nociceptive TRP channels initially result in increased Ca²⁺ entry to activate death signals which oxidize and degrade proteins and induce DNA fragmentation

Decreased intracellular K⁺ concentration in primary cells alters water structure from bound water to free water; it could be due to the K⁺ content directly affecting bound water structure. The structure of bound water is similar to an iceberg, and the melting rate of an iceberg can be determined by K⁺ content [31]. Accordingly, decreased intracellular K⁺ concentration by activation of Ca²⁺-activated K⁺ channels in primary cells may interrupt the bound water structure, similar to the melting iceberg. Furthermore, we consider how Ca²⁺ signaling from nociceptive TRP channels activates these K⁺ channels to alter water structure. TRP channels, when activated, contribute to cell depolarization via allowing Na⁺ to flow into the cell [16]. Similarly, Xenopus oocytes revealed a depolarization of the membrane potential by fertilization, which induces Na⁺ entry [32]. Thus, the active nociceptive TRP channels upon continuous environmental stimuli induce Na⁺ entry, which initially causes an increase in intracellular proton signaling, especially Ca²⁺ signaling; Ca²⁺-activated K⁺ channels to decrease the intracellular K⁺ concentration, then the water state is changed gradually from the bound state to the free state.

As shown in Figure 1, once Ca²⁺ signaling from active nociceptive TRP channels activates K⁺ channels to continuously release the cell cycle, the repair system quickly recovers errors to maintain tissue homeostasis. The repair system could be driven by the p53 family proteins first, and then induce death signals following resistance to tumorigenesis. The cell dynamic alternation between death and survival might be balanced until dysfunction of the repair system, especially p53 family proteins. The switch between cell death and tumorigenesis may be the SIR, which is thought to be a contributor towards tumorigenesis with genomic instability and dysfunction of the repair system [3]. Accumulation of intracellular ROS and DDR results in genomic instability and dysfunction of the repair system, followed by a change in the activity of proto-oncogenes and tumor suppressor genes to accelerate cancer development.

Ca2+ signaling from nociceptive TRP channels promotes cancer progression

We pointed out that Ca²⁺ signaling from nociceptive TRP channels is involved in initiating cancer progression. More evidence of nociceptive TRP channels is shown in regulating cancer promotion, because Ca²⁺ signaling is necessary for cancer cell growth, metastasis and chemotherapy resistance [33]. The Ca²⁺ dependent activation of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) phosphorylates multiple targets, including focal adhesion kinase (FAK) which accelerates cancer cell migration and Akt, c-Jun N-terminal Kinase (JNK) and Src which promotes cancer cell proliferation [34]. CaMKII-dependent activation of hypoxia-inducible factor 1-alpha (HIF-1α) and P-glycoprotein prevents cancer cells from chemotherapy drug-induced cell death [35]. As shown in Table 2, nociceptive TRP channels are upregulated in many types of cancer cells. TRPA1 and TRPC5 perform an important role in transducing chemical nociceptive stimuli [36], but upregulated TRPA1 and TRPC5 reveal poor prognosis in cancers. TRPC1 and TRPC6 channels, which are involved in nociceptive pathways, cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization [37]. TRPC1, TRPC6 and TRPV4 have been implicated in upregulation of breast and gastric cancer. TRPC6 also controls glioma development via regulation of G2/M phase transition [38]. TRPC3 and TRPC7 have recently been reported to be correlated with nociceptive pain in rodents [13, 39]. Although TRPC3 and TRPC7 mediate store-operated Ca²⁺ entry (SOCE) potentiating acceleration of cancer cell growth [13, 40], seldom does the study point out the function of TRPC7 in cancer development.

Table 2.

Nociceptive TRP channels in regulating cancer progression

Channel	Tumor types	Tumor cells vs. Normal controls	Pathological function in cancer	Prognosis	Reference
TRPA1	Breast cancer, lung cancer, pancreatic cancer, nasopharyngeal carcinoma	Over-expression	Promote cancer cell survival against chemotherapeutic agents	Unfavorable in breast cancer, lung cancer, nasopharyngeal carcinoma	[82, 89, 90]
TRPC1	Breast cancer (PTEN-deficient type), lung cancer, gastric cancer, pancreatic cancer, colorectal cancer, glioblastoma	Over-expression	Promote cancer cell growth and metastasis	Unfavorable in breast cancer (PTEN-deficient type), gastric cancer	[91, 92]
TRPC3	Breast cancer (triple negative type), ovarian cancer	Over-expression	Promote cancer cell growth and cancer cell survival against chemotherapeutic agents	Unfavorable in breast cancer, ovarian cancer	[40, 93]
TRPC5	Breast cancer, colorectal cancer	Over-expression	Promote cancer cell survival against chemotherapeutic agents, tumor metastasis	Unfavorable in colorectal cancer	[94, 95]
TRPC6	Breast cancer, hepatoma, gastric cancer, ESCC, prostate cancer, glioblastoma	Over-expression	Promote cancer cell growth and metastasis	Unfavorable in esophageal squamous cell carcinoma	[96–101]
TRPC7	Lung cancer, skin sarcoma	Over-expression	Promote cancer cell growth	Not investigated	[13]
TRPM2	Breast cancer, lung cancer, gastric cancer, pancreatic cancer, prostate cancer, HCC, oral cancer, glioblastoma	Over-expression, mutant type in PDAC, long non-coding RNA TRPM2-AS in HCC	Promote cancer cell growth and metastasis	Unfavorable in luminal B and TP53 wild type breast cancer, lung cancer, PDAC, HCC (Long non-coding RNA TRPM2-AS)	[45, 102–107]
TRPM3	ccRCC, glioblastoma, choroid plexus papilloma	Over-expression	Promote cancer cell growth	Not investigated	[107–109]
TRPM8	Breast cancer, lung cancer, gastric cancer, ESCC, pancreatic cancer, prostate cancer, HCC, esophageal cancer, glioblastoma, neuroblastoma, urinary bladder carcinoma	Over-expression	Promote cancer cell survival against chemotherapeutic agents, cancer cell growth and metastasis	Unfavorable in urinary bladder carcinoma	[110–113]
TRPV1	Breast cancer, oral cancer, glioblastoma	Over-expression	Promote cancer cell growth	Unfavorable in breast cancer	[107, 114, 115]
TRPV2	Breast cancer, gastric cancer, ESCC, prostate cancer, HCC, ovarian cancer, oral cancer, glioblastoma, hematological cancer, urinary bladder carcinoma	Over-expression, full-length TRPV2 (f-TRPV2) in urinary bladder carcinoma	Promote cancer cell growth and metastasis	Unfavorable in multiple myeloma, ESCC	[46, 107, 111, 116, 117]
TRPV3	Breast cancer, lung cancer, oral cancer	Over-expression	Promote cancer cell growth and metastasis	Not investigated	[111, 116, 118]
TRPV4	Breast cancer, gastric cancer, pancreatic cancer, HCC, colorectal cancer, oral cancer, glioblastoma	Over-expression	Promote cancer cell growth and metastasis	Unfavorable in gastric cancer	[93, 111, 116, 119–122]

ESCC: esophageal squamous cell carcinoma; PTEN: phosphatase and Tensin Homolog deleted on Chromosome 10; PDAC: pancreatic ductal adenocarcinoma; HCC: hepatocellular carcinoma; ccRCC: clear cell renal cell carcinoma

TRPM2, TRPM3 and TRPM8 have a pathological role for a wide range of inflammatory conditions and neuropathic pain [36], and also belong to thermosensitive TRP channels [41, 42]. Those nociceptive TRPMs with overexpression facilitate malignancy in a majority of cancers (Table 2). TRPV1, nociceptor, causes pain hypersensitivity associated with neuropathic pain, peripheral inflammation [43] and cancer cell growth and metastasis (Table 2). Furthermore, long non-coding RNA, an antisense transcript of TRPM2 (TRPM2-AS), is overexpressed in prostate cancer and thought to be linked to poor prognosis [44]. The mutated TRPM2 gene also reveals a marked negative correlation with patient survival rate compared with the normal control group [45]. Upregulation of full-length glycosylated TRPV2 protein (f-TRPV2) in urinary bladder carcinoma is associated with metastatic ability, which can be regulated by short splice variant of TRPV2 (s-TRPV2). f-TRPV2 and s-TRPV2 have opposite trends of expression in cancer cells compared to normal cells [46]. Therefore, nociceptive TRP channels potentiate initiation of cancer progression and promote cancer development and malignancy.

Epigenetic mechanisms seem to promote expression of nociceptive TRP channels in cancer cells

Ca²⁺ signaling is a regulator of pathways vital in cancer progression, enhancing cancer cell growth, metastatic ability and cell death resistance [47]. To maintain cancer development, malignant cells tend to alter expression of Ca²⁺ homeostasis genes via regulating epigenetic mechanisms [48]. Therefore, overexpression of nociceptive TRP channels in cancers is due to epigenetic regulation to sustain cancer development. We previously mentioned that active nociceptive TRP channels potentiates activation of Ca²⁺-activated K⁺ channels to reduce the intracellular K⁺ concentration, which releases cell proliferation by releasing the cell cycle and the intracellular water structure; chromosome structure could become much less tightly packed and lead to epigenetic regulation via free ions and proteins [49].

Three epigenetic mechanisms are categorized as writers, readers and erasers [50]. Writers that introduce various chemical modifications in DNA and histones, for instance, increased histone H3 acetylation of the TRPV1 promoter region with histone acetyltransferases (HATs) resulting in upregulated levels of TRPV1 in dorsal root ganglia that ultimately induces hyperalgesia in rats [51]. Overexpression of TRPV1 is reportedly involved in both tumor growth and cancer-induced pain [52]. Indeed, the nociceptive TRP channel also induces Ca²⁺ signaling to produce a snowball effect that activates Ca²⁺ dependent transcription factors to accelerate its expression. Readers have a specialized domain containing proteins that identify and interpret those modifications. Ca²⁺ signaling from TRPV6 activates Ca²⁺-dependent calcineurin-nuclear factor of activated T (NFAT) cells which in turn influences translocation of TRPC6 promoter to upregulate TRPC6 during pathologic cardiac remodeling [53]. TRPC6 may be overexpressed in cancers due to activating the TRPC6-NFAT pathway [54].

Erasers are the dedicated group of enzymes proficient in removing these chemical tags; most enzymes are histone deacetylase complexes (HDACs) and these play an essential role in maintaining genomic stability in cells [55]. HDACs remove acetyl groups and lead to a more closed chromatin structure, generally associated with transcriptional repression. During cancer progression, deficient HDACs activity regulates the expression and activity of numerous proteins [56]. Therefore, interruption of the histone variant macroH2A-recruited HDAC1 and HDAC2 augments overexpression of TRPC3 and TRPC6 via histone acetylation, resulting in increased cell growth and invasion in bladder cancer cells [57]. Although malignant cells potentiate intensive epigenetic regulation to upregulate nociceptive TRP channels in maintaining cancer development, the epigenetic mechanisms of nociceptive TRP channels activation in cancers needs to be further investigated.

Despite the prevalence of aging-associated cancer development, several types of cancer, especially retinoblastoma (RB), occurs mostly in the young. Epigenetic regulation of RB plays an important role in determining RB development, because extensive DNA methylation of RB promoter, RB1 mutations and macrodeletions have been reported in RB [58, 59]. TRPV1 as well as TRPM8 are expressed in RB, and serve as prognostic factors for RB progression [60]. TRPV1-associated DNA (cytosine-5-)-methyltransferase 1 (DNMT1) activation increases methylation of genes that regulatevisceral pain sensationin the peripheral nervous system of rats [51], and it potentiates regulation of extensive DNA methylation in RB promoter. Besides, epigenetic modifications contribute to heritable changes in gene expression without altering the DNA sequence, but they can also lead to gene mutations [61]. Hypermethylation of genes mostly occurs as mutations in cancers, especially tumor suppressor genes or DNA repair genes [62]. It is still unknown whether TRPV1 or TRPM8 is involved in controlling germline mutations of epigenetic modifiers in RB, yet Ca²⁺ signaling from nociceptive TRP channels may influence epigenetic mechanisms in determining non-aging-associated cancer development.

Targeting nociceptive TRP channels prohibits cancer development

The role of nociceptive TRP channels in regulating cancer progression illustrates that excess Ca²⁺ signaling from active nociceptive TRP channels upon continual environmental stimuli induces the aging process and may ultimately lead to cancer progression. Consequently, blockage of excess Ca²⁺ signaling from active nociceptive TRP channels facilitates inhibition of aging-associated cancer development (Figure 2). Derinat (sodium deoxyribonucleate) protects skin against UVB-induced cellular damage and aging via inhibiting TRPCs, especially nociceptive TRPC7 [63], which reportedly mediates aging-associated tumorigenesis induced by UVB [13]. Quenching of ROS accumulation and inflammatory response by therapeutic antioxidants, such as hydrogen-rich (H₂) water, resveratrol or sesamol significantly eliminates the aging process and thus protects against cancer development [64–66]. Although nonsteroidal anti-inflammatory drugs (NSAIDs) with anti-inflammatory effects prohibit aging-associated cancer development by inducting death signals [3], they also elicit increased ROS level in different cell types [67]. The proapoptotic accumulation of ROS in both yeast and mammalian cells is elicited by NSAIDs [68].

Figure 2

Schematic representation of nociceptive TRP channels in regulating the aging-associated cancer development and the strategic targeting of its process. Nociceptive TRP channels respond to specific environmental stimuli, such as microbes, chemicals, physical injuries, inducing excess Ca²⁺ signaling from active nociceptors upon continual environmental stimuli in the aging process. Blockage of the aging process which is induced by active nociceptive TRP channels and trigger of repair system provide a novel strategy for preventing cancer development

Cancer is an aging-associated disease. Despite blockage of active nociceptive TRP channels and ROS accumulation, the potential for cancer is not wholly eliminated. According to our pervious study, 55.8% of gene mutations occurred through the natural process of aging, and an external trigger such as environmental stimulus is required for aging-associated diseases, especially cancer [13]. DNA repair systems are inactivated and dysregulated due to genomic instability. Recently, the nucleotide precursor of nicotinamide adenine dinucleotide (NAD), nicotinamide mononucleotide (NMN), has been reported to enhance DNA damage repair and maintain mitochondrial homeostasis [69], and activates stem cells for the increase of their self-renewal [70] and the maintenance of their pluripotency [71]. Long-term administration of NMN decreases age-associated physiological degeneration in mice [72]. Similarly, mesenchymal stem cell (MSC)-derived exosomes have potential for cell-free repair for a variety of diseases and injuries through activating DNA damage repair and tissue regeneration [73]. MSC-exosomes, which carry proteins, lipids, DNA, and RNA from MSCs, have biological functions similar to MSCs, but have a smaller volume, can penetrate biofilms, have low immunogenicity, and can be stored [74].

Once cancer development is initiated by epigenetic mechanisms, cancer evolution creates malignant cells and induces changes in the genome [75]; at this stage, NMN and MSC-exosomes oppositely promote cancer progression, maintaining cancer cell growth and metastasis [76, 77]. For treating cancer cells, targeting nociceptive TRP channel activities by using multiple TRP-specific antagonists facilitates elimination or reduction of cancer development; for instance, treatment with SKF96365 and 2-aminoethoxydiphenylborate (2-APB) blocks lung cancer cell growth via inhibiting nociceptive TRPC1 [13]. Functional expression of TRPM8 in prostate carcinoma can be blocked by N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), clotrimazole, and DD01050 following decrease of cell growth [33]. TRPV1 activity, which is inhibited by melatonin, prevents breast cancer cells from doxorubicin-induced cell death [78]. Furthermore, because of upregulated nociceptive TRP channels in cancer cells, overactivation of TRP channels by treating their agonists results in huge ROS accumulation and induces cell death signals. Applying TRPV1 agonist capsaicin in breast cancer and glioblastoma contributes to cell apoptosis due to mitochondria Ca²⁺ overloading-increased ROS level [78–80]. But treatment with agonists of nociceptive TRP channels in several cancer cells also accelerates their malignancy and chemotherapy resistance [33].

Conclusions

This review suggests a dual role of nociceptive TRP channels in regulating cancer progression, initiating cancer progression by aging-induced genomic instability, and promoting malignancy by epigenetic regulation. Excess Ca²⁺ signaling from active nociceptive TRP channels under continuous environmental stimuli induces intracellular ROS accumulation and DDR, which triggers the SIR and SASP activation, leading to genomic instability and cancer progression. Additionally, to maintain cancer development, cancer cells tend to alter expression of Ca²⁺ homeostasis genes via regulating epigenetic mechanisms. Nociceptive TRP channels are upregulated in many types of cancer cells and promote cancer cell growth, metastasis and chemotherapy resistance. Consequently, we propose a novel strategy for treating cancer: blockage of nociceptive TRP channels in the aging process prevents cancer initiation, and targeting nociceptive TRP channels in cancer cells provide potential therapies to prohibit cancer progression.

Abbreviations

DDR:

DNA damage response

ESCC:

esophageal squamous cell carcinoma

GPCR:

G protein-coupled receptors

HCC:

hepatocellular carcinoma

HDACs:

histone deacetylase complexes

MSC:

mesenchymal stem cell

NMN:

nicotinamide mononucleotide

RB:

retinoblastoma

ROS:

reactive oxygen species

SIR:

senescence inflammation response

TRP:

transient receptor potential

TRPA:

transient receptor potential ankyrin

TRPC:

transient receptor potential canonical

TRPM:

transient receptor potential mucolipin

TRPM2-AS:

antisense transcript of transient receptor potential mucolipin 2

TRPV:

transient receptor potential vanilloid

UVB:

ultraviolet B

Declarations Author contributions

WLH, writing—original draft preparation; MN, review and editing; EI, review and editing; TY, supervision.

Conflicts of interest

The authors declare no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by Ministry of Science and Technology of Taiwan, MOST 109-2314-B-037-143. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References 1.

Siegel

Miller

Jemal

Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30. 10.3322/caac.21442

29313949

Nag

Qin

Srivenugopal

Wang

Zhang

The MDM2-p53 pathway revisited. J Biomed Res. 2013;27:254–71. 10.7555/JBR.27.20130030

23885265

PMC3721034

Pribluda

Elyada

Wiener

Hamza

Goldstein

Biton

A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell. 2013;24:242–56. 10.1016/j.ccr.2013.06.005

23890787

Schumacher

DNA damage responses and p53 in the aging process. Blood. 2018;131:488–95. 10.1182/blood-2017-07-746396

29141944

PMC6839964

Barja

Updating the mitochondrial free radical theory of aging: an integrated view, key aspects, and confounding concepts. Antioxid Redox Signal. 2013;19:1420–45. 10.1089/ars.2012.5148

23642158

PMC3791058

Adam-Vizi

Starkov

AA.

Calcium and mitochondrial reactive oxygen species generation: how to read the facts. J Alzheimers Dis. 2010;20 Suppl 2:S413–26. 10.3233/JAD-2010-100465

20421693

PMC3056350

Bong

AHL

Monteith

GR.

Calcium signaling and the therapeutic targeting of cancer cells. Biochim Biophys Acta Mol Cell Res. 2018;1865:1786–94. 10.1016/j.bbamcr.2018.05.015

29842892

Santoni

Morelli

Marinelli

Nabissi

Santoni

Amantini

Calcium signaling and the regulation of chemosensitivity in cancer cells: role of the transient receptor potential channels. Adv Exp Med Biol. 2020;1131:505–17. 10.1007/978-3-030-12457-1_20

31646523

Roberts-Thomson

Chalmers

Monteith

GR.

The calcium-dignaling toolkit in cancer: remodeling and targeting. Cold Spring Harb Perspect Biol. 2019;11:a035204. 10.1101/cshperspect.a035204

31088826

PMC6671942

10.

Gregório

Soares-Lima

Alemar

Recamonde-Mendoza

Camuzi

de Souza-Santos

Calcium signaling alterations caused by epigenetic mechanisms in pancreatic cancer: from early markers to prognostic impact. Cancers (Basel). 2020;12:1735. 10.3390/cancers12071735

11.

Riera

Huising

Follett

Leblanc

Halloran

Van Andel

TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Cell. 2014;157:1023–36. 10.1016/j.cell.2014.03.051

24855942

12.

Borbély

Payrits

Hunyady

Mező

Pintér

Important regulatory function of transient receptor potential ankyrin 1 receptors in age-related learning and memory alterations of mice. Geroscience. 2019;41:643–54. 10.1007/s11357-019-00083-1

31327098

PMC6885083

13.

Hsu

Tsai

Liang

Kahle

Nociceptive transient receptor potential canonical 7 (TRPC7) mediates aging-associated tumorigenesis induced by ultraviolet B. Aging Cell. 2020;19:e13075. 10.1111/acel.13075

31755176

PMC6974716

14.

Alcalde

Iñigo-Portugués

González-González

Almaraz

Artime

Morenilla-Palao

Morphological and functional changes in TRPM8-expressing corneal cold thermoreceptor neurons during aging and their impact on tearing in mice. J Comp Neurol. 2018;526:1859–74. 10.1002/cne.24454

29664111

15.

Duitama

Vargas-Lopez

Casas

Albarracin

Sutachan

Torres

YP.

TRP channels role in pain associated with neurodegenerative diseases. Front Neurosci. 2020;14:782. 10.3389/fnins.2020.00782

32848557

PMC7417429

16.

Venkatachalam

Montell

TRP channels. Annu Rev Biochem. 2007;76:387–417. 10.1146/annurev.biochem.75.103004.142819

17579562

PMC4196875

17.

Prevarskaya

Zhang

Barritt

TRP channels in cancer. Biochim Biophys Acta. 2007;1772:937–46. 10.1016/j.bbadis.2007.05.006

17616360

18.

Mickle

Shepherd

Mohapatra

DP.

Nociceptive TRP channels: sensory detectors and transducers in multiple pain pathologies. Pharmaceuticals (Basel). 2016;9:72. 10.3390/ph9040072

19.

Gonzalez-Ramirez

Chen

Liedtke

Morales-Lazaro

SL.

TRP Channels and Pain. In: Emir

TLR

editor. Neurobiology of TRP channels. Boca Raton (FL): CRC Press/Taylor & Francis; 2017. pp. 125–48.

20.

Milici

Talavera

TRP channels as cellular targets of particulate matter. Int J Mol Sci. 2021;22:2783. 10.3390/ijms22052783

33803491

PMC7967245

21.

Veldhuis

Poole

Grace

McIntyre

Bunnett

NW.

The G protein-coupled receptor-transient receptor potential channel axis: molecular insights for targeting disorders of sensation and inflammation. Pharmacol Rev. 2015;67:36–73. 10.1124/pr.114.009555

25361914

22.

Miller

Zhang

TRP channels as mediators of oxidative stress. Adv Exp Med Biol. 2011;704:531–44. 10.1007/978-94-007-0265-3_29

21290315

23.

Cuollo

Antonangeli

Santoni

Soriani

The senescence-associated secretory phenotype (SASP) in the challenging future of cancer therapy and age-related diseases. Biology (Basel). 2020;9:485. 10.3390/biology9120485

33371508

PMC7767554

24.

Yang

Hsu

Yoshoioka

A novel concept on the repetitive calcium elevation. In: Yamaguchi

editor. Recent developments in calcium signaling. New York: Nova Science Publishers, Inc.; 2014. pp. 67–87.

25.

Kunzelmann

Ion channels and cancer. J Membr Biol. 2005;205:159–73. 10.1007/s00232-005-0781-4

16362504

26.

Lehen’kyi

Shapovalov

Skryma

Prevarskaya

Ion channels and transporters in cancer. 5. Ion channels in control of cancer and cell apoptosis. Am J Physiol Cell Physiol. 2011;301:C1281–9. 10.1152/ajpcell.00249.2011

21940667

27.

Ito

Hsu

Yoshioka

A role for proton signaling in the induction of somatic cells to pluripotent embryonic stem cells. J Phys Chem Biophys. 2014;4:1000138.

28.

Lang

Stournaras

Ion channels in cancer: future perspectives and clinical potential. Philos Trans R Soc Lond B Biol Sci. 2014;369:20130108. 10.1098/rstb.2013.0108

24493756

PMC3917362

29.

Wijerathne

Kim

Yang

Lee

KP.

Intracellular calcium-dependent regulation of the sperm-specific calcium-activated potassium channel, hSlo3, by the BK_Ca activator LDD175. Korean J Physiol Pharmacol. 2017;21:241–9. 10.4196/kjpp.2017.21.2.241

28280418

PMC5343058

30.

Merta

Fullerton

Cameron

IL.

Characterization of water in unfertilized and fertilized sea urchin eggs. J Cell Physiol. 1986;127:439–47. 10.1002/jcp.1041270313

3011815

31.

Wang

Han

Zhang

Experimental study on the effect of potassium chloride’s content on the ice melting rate. IOP Conf Ser: Earth Environ Sci. 2018;170:052020. 10.1088/1755-1315/170/5/052020

32.

Webb

Nuccitelli

Direct measurement of intracellular pH changes in Xenopus eggs at fertilization and cleavage. J Cell Biol. 1981;91:562–7. 10.1083/jcb.91.2.562

6796594

PMC2111970

33.

Santoni

Maggi

Morelli

Santoni

Marinelli

Transient receptor potential cation channels in cancer therapy. Med Sci (Basel). 2019;7:108. 10.3390/medsci7120108

34.

Wang

Zhao

Zhe

The emerging role of CaMKII in cancer. Oncotarget. 2015;6:11725–34. 10.18632/oncotarget.3955

25961153

PMC4494900

35.

Riganti

Doublier

Viarisio

Miraglia

Pescarmona

Ghigo

Artemisinin induces doxorubicin resistance in human colon cancer cells via calcium-dependent activation of HIF-1alpha and P-glycoprotein overexpression. Br J Pharmacol. 2009;156:1054–66. 10.1111/j.1476-5381.2009.00117.x

19298255

PMC2697684

36.

Aroke

Powell-Roach

Jaime-Lara

Tesfaye

Roy

Jackson

Taste the pain: the role of TRP channels in pain and taste perception. Int J Mol Sci. 2020;21:5929. 10.3390/ijms21165929

37.

Alessandri-Haber

Dina

Chen

Levine

JD.

TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization. J Neurosci. 2009;29:6217–28. 10.1523/JNEUROSCI.0893-09.2009

19439599

PMC2726836

38.

Ding

Zhou

Cheng

Yao

Essential role of TRPC6 channels in G2/M phase transition and development of human glioma. J Natl Cancer Inst. 2010;102:1052–68. 10.1093/jnci/djq217

20554944

39.

Quick

Zhao

Eijkelkamp

Linley

Rugiero

Cox

TRPC3 and TRPC6 are essential for normal mechanotransduction in subsets of sensory neurons and cochlear hair cells. Open Biol. 2012;2:120068. 10.1098/rsob.120068

22724068

PMC3376737

40.

Wang

Tsang

SY.

TRPC3 regulates the proliferation and apoptosis resistance of triple negative breast cancer cells through the TRPC3/RASA4/MAPK pathway. Cancers (Basel). 2019;11:558. 10.3390/cancers11040558

41.

Ota

Nakane

Kashio

Suzuki

Nakamura

Mori

Involvement of TRPM2 and TRPM8 in temperature-dependent masking behavior. Sci Rep. 2019;9:3706. 10.1038/s41598-019-40067-x

30842533

PMC6403366

42.

Kelemen

Pinto

Kim

Lisztes

Hanyicska

Vladar

The TRPM3 ion channel mediates nociception but not itch evoked by endogenous pruritogenic mediators. Biochem Pharmacol. 2021;183:114310. 10.1016/j.bcp.2020.114310

33130130

PMC8086171

43.

Levine

Alessandri-Haber

TRP channels: targets for the relief of pain. Biochim Biophys Acta. 2007;1772:989–1003. 10.1016/j.bbadis.2007.01.008

17321113

44.

Orfanelli

Jachetti

Chiacchiera

Grioni

Brambilla

Briganti

Antisense transcription at the TRPM2 locus as a novel prognostic marker and therapeutic target in prostate cancer. Oncogene. 2015;34:2094–102. 10.1038/onc.2014.144

24931166

45.

Lin

Wang

Chen

Liu

Xiao

Wang

TRPM2 promotes the proliferation and invasion of pancreatic ductal adenocarcinoma. Mol Med Rep. 2018;17:7537–44. 10.3892/mmr.2018.8816

29620272

PMC5983953

46.

Siveen

Nizamuddin

Uddin

Al-Thani

Frenneaux

Janahi

TRPV2: a cancer biomarker and potential therapeutic target. Dis Markers. 2020;2020:8892312. 10.1155/2020/8892312

33376561

PMC7746447

47.

Shapovalov

Ritaine

Skryma

Prevarskaya

Role of TRP ion channels in cancer and tumorigenesis. Semin Immunopathol. 2016;38:357–69. 10.1007/s00281-015-0525-1

26842901

48.

Izquierdo-Torres

Hernández-Oliveras

Fuentes-García

Zarain-Herzberg

Á.

Calcium signaling and epigenetics: a key point to understand carcinogenesis. Cell Calcium. 2020;91:102285. 10.1016/j.ceca.2020.102285

32942140

49.

Margueron

Reinberg

Chromatin structure and the inheritance of epigenetic information. Nat Rev Genet. 2010;11:285–96. 10.1038/nrg2752

20300089

PMC3760772

50.

Biswas

Rao

CM.

Epigenetic tools (The Writers, The Readers and The Erasers) and their implications in cancer therapy. Eur J Pharmacol. 2018;837:8–24. 10.1016/j.ejphar.2018.08.021

30125562

51.

Hong

Zheng

Wiley

JW.

Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system. Gastroenterology. 2015;148:148–57.e7. 10.1053/j.gastro.2014.09.032

25263804

PMC4274248

52.

Akari

Tadashi

Yuichi

Tomoyuki

Masatoshi

Tomoyuki

TRPV1 is involved in both tumor growth and cancer-induced pain. American Society of Anesthesiologists 2019: The anesthesiology annual meeting; 2019 Oct 20; Florida, USA.

53.

Kuwahara

Wang

McAnally

Richardson

Bassel-Duby

Hill

TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J Clin Invest. 2006;116:3114–26. 10.1172/JCI27702

17099778

PMC1635163

54.

Kim

Hwang

Eom

Kim

Park

Jeong

WNK1 promotes renal tumor progression by activating TRPC6-NFAT pathway. FASEB J. 2019;33:8588–99. 10.1096/fj.201802019RR

31022353

55.

Lahue

Frizzell

Histone deacetylase complexes as caretakers of genome stability. Epigenetics. 2012;7:806–10. 10.4161/epi.20922

22722985

PMC3427275

56.

Glozak

Seto

Histone deacetylases and cancer. Oncogene. 2007;26:5420–32. 10.1038/sj.onc.1210610

17694083

57.

Kim

Heo

Choi

Kim

The histone variant MacroH2A regulates Ca²⁺ influx through TRPC3 and TRPC6 channels. Oncogenesis. 2013;2:e77. 10.1038/oncsis.2013.40

24165580

PMC3816217

58.

Dimaras

Corson

TW.

Retinoblastoma, the visible CNS tumor: a review. J Neurosci Res. 2019;97:29–44. 10.1002/jnr.24213

29314142

PMC6034991

59.

Benavente

Dyer

MA.

Genetics and epigenetics of human retinoblastoma. Annu Rev Pathol. 2015;10:547–62. 10.1146/annurev-pathol-012414-040259

25621664

60.

Mergler

Cheng

Skosyrski

Garreis

Pietrzak

Kociok

Altered calcium regulation by thermosensitive transient receptor potential channels in etoposide-resistant WERI-Rb1 retinoblastoma cells. Exp Eye Res. 2012;94:157–73. 10.1016/j.exer.2011.12.002

22182671

61.

Tieva

Peltomäki

Epigenetic modifications in cancer. Duodecim. 2012;128:62–71. (in Finnish) 22312828

62.

Lee

Ahn

Jeong

Pak

Moon

Kim

Impact of mutations in DNA methylation modification genes on genome-wide methylation landscapes and downstream gene activations in pan-cancer. BMC Med Genomics. 2020;13 Suppl 3:27. 10.1186/s12920-020-0659-4

32093698

PMC7038532

63.

Hsu

Noda

Liu

Sakakibara

Derinat protects skin against ultraviolet-B (UVB)-induced cellular damage. Molecules. 2015;20:20297–311. 10.3390/molecules201119693

26569211

PMC6331914

64.

Yang

Zhu

Anti-inflammatory and antitumor action of hydrogen via reactive oxygen species. Oncol Lett. 2018;16:2771–6. 10.3892/ol.2018.9023

30127861

PMC6096066

65.

Salehi

Mishra

Nigam

Sener

Kilic

Sharifi-Rad

Resveratrol: a double-edged sword in health benefits. Biomedicines. 2018;6:91. 10.3390/biomedicines6030091

66.

Aquino

LBB

Barbaza

MYU

Hsieh

Castro-Cruz

Yang

Anti-inflammatory and anticancer properties of bioactive compounds from Sesamum indicum L.—a review. Molecules. 2019;24:4426. 10.3390/molecules24244426

67.

Ghosh

Alajbegovic

Gomes

AV.

NSAIDs and cardiovascular diseases: role of reactive oxygen species. Oxid Med Cell Longev. 2015;2015:536962. 10.1155/2015/536962

26457127

PMC4592725

68.

Bhattacharyya

Ghosh

Sil

PC.

Amelioration of aspirin induced oxidative impairment and apoptotic cell death by a novel antioxidant protein molecule isolated from the herb Phyllanthus niruri. PLoS One. 2014;9:e89026. 10.1371/journal.pone.0089026

24586486

PMC3929659

69.

Croteau

Fang

Nilsen

Bohr

VA.

NAD⁺ in DNA repair and mitochondrial maintenance. Cell Cycle. 2017;16:491–2. 10.1080/15384101.2017.1285631

28145802

PMC5384578

70.

Song

Yang

Ning

Zhen

Nicotinamide mononucleotide promotes osteogenesis and reduces adipogenesis by regulating mesenchymal stromal cells via the SIRT1 pathway in aged bone marrow. Cell Death Dis. 2019;10:336. 10.1038/s41419-019-1569-2

31000692

PMC6472410

71.

Meng

Ren

Zhou

Song

Wang

Nicotinamide promotes cell survival and differentiation as kinase inhibitor in human pluripotent stem cells. Stem Cell Reports. 2018;11:1347–56. 10.1016/j.stemcr.2018.10.023

30503259

PMC6294242

72.

Mills

Yoshida

Stein

Grozio

Kubota

Sasaki

Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016;24:795–806. 10.1016/j.cmet.2016.09.013

28068222

PMC5668137

73.

Kim

Choi

Kim

Mesenchymal stem cell-derived exosomes for effective cartilage tissue repair and treatment of osteoarthritis. Biotechnol J. 2020;15:e2000082. 10.1002/biot.202000082

32559340

74.

Liu

Zhang

Yuan

Wang

Exosomes: a novel therapeutic agent for cartilage and bone tissue regeneration. Dose Response. 2019;17:1559325819892702. 10.1177/1559325819892702

75.

Zhou

Zhang

Wang

Evolving insights: how DNA repair pathways impact cancer evolution. Cancer Biol Med. 2020;17:805–27. 10.20892/j.issn.2095-3941.2020.0177

33299637

PMC7721097

76.

Zhao

Chen

Song

Bie

Zhang

Dual role of MSC-derived exosomes in tumor development. Stem Cells Int. 2020;2020:8844730. 10.1155/2020/8844730

32963552

PMC7499322

77.

Chiarugi

Dolle

Felici

Ziegler

The NAD metabolome-a key determinant of cancer cell biology. Nat Rev Cancer. 2012;12:741–52. 10.1038/nrc3340

23018234

78.

Chen

Chiang

Xiao

Chen

Zhao

The impact of TRPV1 on cancer pathogenesis and therapy: a systematic review. Int J Biol Sci. 2021;17:2034–49. 10.7150/ijbs.59918

34131404

PMC8193258

79.

Weber

Al-Refae

Wölk

Bonatz

Altmüller

Becker

Expression and functionality of TRPV1 in breast cancer cells. Breast Cancer (Dove Med Press). 2016;8:243–52. 10.2147/BCTT.S121610

28008282

PMC5167528

80.

Amantini

Mosca

Nabissi

Lucciarini

Caprodossi

Arcella

Capsaicin-induced apoptosis of glioma cells is mediated by TRPV1 vanilloid receptor and requires p38 MAPK activation. J Neurochem. 2007;102:977–90. 10.1111/j.1471-4159.2007.04582.x

17442041

81.

Boonen

Alpizar

Meseguer

Talavera

TRP channels as sensors of bacterial endotoxins. Toxins (Basel). 2018;10:836. 10.3390/toxins10080326

82.

Yen

Chan

Chen

Lee

Overexpression of transient receptor protein cation channel subfamily a member 1, confers an independent prognostic indicator in nasopharyngeal carcinoma. J Cancer. 2016;7:1181–8. 10.7150/jca.15326

27390592

PMC4934025

83.

Casciano

Duchemin

Lamontagne

Steel

Bouchard

MJ.

Hepatitis B virus modulates store-operated calciumentrytoenhanceviral replicationin primary hepatocytes. PLoS One. 2017;12:e0168328. 10.1371/journal.pone.0168328

28151934

PMC5289456

84.

Goldenberg

Wang

Ranke

Liedtke

Tabuchi

Kuebler

WM.

TRPV4 is required for hypoxic pulmonary vasoconstriction. Anesthesiology. 2015;122:1338–48. 10.1097/ALN.0000000000000647

25815455

85.

Steinritz

Stenger

Dietrich

Gudermann

Popp

TRPs in tox: involvement of transient receptor potential-channels in chemical-induced organ toxicity—a structured review. Cells. 2018;7:98. 10.3390/cells7080098

86.

Ernst

Grabiec

Falk

Dehghani

Schaedlich

The endocrine disruptor DEHP and the ECS: analysis of a possible crosstalk. Endocr Connect. 2020;9:101–10. 10.1530/EC-19-0548

31910153

PMC6993259

87.

Liu

Montell

Forcing open TRP channels: mechanical gating as a unifying activation mechanism. Biochem Biophys Res Commun. 2015;460:22–5. 10.1016/j.bbrc.2015.02.067

25998730

PMC4441759

88.

Bellono

Kammel

Zimmerman

Oancea

UV light phototransduction activates transient receptor potential A1 ion channels in human melanocytes. Proc Natl Acad Sci U S A. 2013;110:2383–8. 10.1073/pnas.1215555110

23345429

PMC3568351

89.

Takahashi

Chen

Harris

Stover

Selfors

Bronson

Cancer cells co-opt the neuronal redox-sensing channel TRPA1 to promote oxidative-stress tolerance. Cancer Cell. 2018;33:985–1003.e7. 10.1016/j.ccell.2018.05.001

29805077

PMC6100788

90.

Cojocaru

Şelescu

Domocoş

Măruţescu

Chiritoiu

Chelaru

Functional expression of the transient receptor potential ankyrin type 1 channel in pancreatic adenocarcinoma cells. Sci Rep. 2021;11:2018. 10.1038/s41598-021-81250-3

33479347

PMC7819973

91.

Elzamzamy

Penner

Hazlehurst

LA.

The role of TRPC1 in modulating cancer progression. Cells. 2020;9:388. 10.3390/cells9020388

92.

Zhang

Ren

Zhao

Ren

TRPC1 exacerbate metastasis in gastric cancer via ciRS-7/miR-135a-5p/TRPC1 axis. Biochem Biophys Res Commun. 2020;529:85–90. 10.1016/j.bbrc.2020.05.181

32560824

93.

Tao

Zhao

Jin

Zhang

Liu

FSH enhances the proliferation of ovarian cancer cells by activating transient receptor potential channel C3. Endocr Relat Cancer. 2013;20:415–29. 10.1530/ERC-12-0005

23580589

PMC3669658

94.

Chen

Zhu

Dong

Zhang

Han

Jin

Overexpression of TrpC5 promotes tumor metastasis via the HIF-1α-Twist signaling pathway in colon cancer. Clin Sci (Lond). 2017;131:2439–50. 10.1042/CS20171069

28864720

95.

Zhang

Liu

Chen

Yao

Jin

TRPC5-induced autophagy promotes drug resistance in breast carcinoma via CaMKKβ/AMPKα/mTOR pathway. Sci Rep. 2017;7:3158. 10.1038/s41598-017-03230-w

28600513

PMC5466655

96.

Guilbert

Dhennin-Duthille

Hiani

Haren

Khorsi

Sevestre

Expression of TRPC6 channels in human epithelial breast cancer cells. BMC Cancer. 2008;8:125. 10.1186/1471-2407-8-125

18452628

PMC2409351

97.

El Boustany

Bidaux

Enfissi

Delcourt

Prevarskaya

Capiod

Capacitative calcium entry and transient receptor potential canonical 6 expression control human hepatoma cell proliferation. Hepatology. 2008;47:2068–77. 10.1002/hep.22263

18506892

98.

Cai

Ding

Zhou

Shi

Ren

Blockade of TRPC6 channels induced G2/M phase arrest and suppressed growth in human gastric cancer cells. Int J Cancer. 2009;125:2281–7. 10.1002/ijc.24551

19610066

99.

Zhang

Wen

Yang

Cai

Yang

Luo

High expression of transient potential receptor C6 correlated with poor prognosis in patients with esophageal squamous cell carcinoma. Med Oncol. 2013;30:607. 10.1007/s12032-013-0607-7

23686700

100.

Yue

Wang

Xiao

Wang

Ren

CS.

Expression of TRPC6 in benign and malignant human prostate tissues. Asian J Androl. 2009;11:541–7. 10.1038/aja.2009.53

19701218

PMC3735007

101.

Chigurupati

Venkataraman

Barrera

Naganathan

Madan

Paul

Receptor channel TRPC6 is a key mediator of Notch-driven glioblastoma growth and invasiveness. Cancer Res. 2010;70:418–27. 10.1158/0008-5472.CAN-09-2654

20028870

102.

Sumoza-Toledo

Espinoza-Gabriel

Montiel-Condado

Evaluation of the TRPM2 channel as a biomarker in breast cancer using public databases analysis. Bol Med Hosp Infant Mex. 2016;73:397–404. 10.1016/j.bmhimx.2016.10.001

29421284

103.

Huang

Qin

Liu

Liang

Chen

Downregulation of a novel long noncoding RNA TRPM2-AS promotes apoptosis in non-small cell lung cancer. Tumour Biol. 2017;39:1010428317691191. 10.1177/1010428317691191

104.

Almasi

Sterea

Fernando

Clements

Marcato

Hoskin

TRPM2 ion channel promotes gastric cancer migration, invasion and tumor growth through the AKT signaling pathway. Sci Rep. 2019;9:4182. 10.1038/s41598-019-40330-1

30862883

PMC6414629

105.

Huang

Zhang

Zhao

Long non-coding RNA TRPM2-AS as a potential biomarker for hepatocellular carcinoma. Ir J Med Sci. 2018;187:621–8. 10.1007/s11845-017-1692-y

29081064

106.

Zhao

Cheng

The overexpressed functional transient receptor potential channel TRPM2 in oral squamous cell carcinoma. Sci Rep. 2016;6:38471. 10.1038/srep38471

28008929

PMC5180100

107.

Alptekin

Eroglu

Tutar

Sencan

Geyik

Ulasli

Gene expressions of TRP channels in glioblastoma multiforme and relation with survival. Tumour Biol. 2015;36:9209–13. 10.1007/s13277-015-3577-x

26088448

108.

Hall

Cost

Hegde

Kellner

Mikhaylova

Stratton

TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma. Cancer Cell. 2014;26:738–53. 10.1016/j.ccell.2014.09.015

25517751

PMC4269832

109.

Santoni

Farfariello

TRP channels and cancer: new targets for diagnosis and chemotherapy. Endocr Metab Immune Disord Drug Targets. 2011;11:54–67. 10.2174/187153011794982068

21348820

110.

Yee

NS.

Roles of TRPM8 Ion channels in cancer: proliferation, survival, and invasion. Cancers (Basel). 2015;7:2134–46. 10.3390/cancers7040882

26512697

PMC4695882

111.

Stoklosa

Borgstrom

Kappel

Peinelt

TRP channels in digestive tract cancers. Int J Mol Sci. 2020;21:1877. 10.3390/ijms21051877

112.

Lan

Zhao

Song

Yuan

Liu

TRPM8 facilitates proliferation and immune evasion of esophageal cancer cells. Biosci Rep. 2019;39:BSR20191878. 10.1042/BSR20191878

31519770

PMC6822499

113.

Zeng

Zhuang

Qin

Hua

Mungur

Identification of the role of TRPM8 in glioblastoma and its effect on proliferation, apoptosis and invasion of the U251 human glioblastoma cell line. Oncol Rep. 2019;42:1517–26. 10.3892/or.2019.7260

31524272

114.

Lozano

Córdova

Marchant

Zúñiga

Ochova

Ramírez-Barrantes

Intracellular aggregated TRPV1 is associated with lower survival in breast cancer patients. Breast Cancer (Dove Med Press). 2018;10:161–8. 10.2147/BCTT.S170208

30410392

PMC6197232

115.

Marincsák

Tóth

Czifra

Márton

Rédl

Tar

Increased expression of TRPV1 in squamous cell carcinoma of the human tongue. Oral Dis. 2009;15:328–35. 10.1111/j.1601-0825.2009.01526.x

19320840

116.

Milevskiy

MJG

Monteith

GR.

Transient receptor potential cation channel subfamily V and breast cancer. Lab Invest. 2020;100:199–206. 10.1038/s41374-019-0348-0

31822791

117.

Ren

Hao

Liu

Wang

Study on the clinical significance of TRPV2 and MMP2 expressions in ovarian cancer. BIOCELL. 2021;45:521–6. 10.32604/biocell.2021.012137

118.

Zhang

Fan

Overexpression of TRPV3 correlates with tumor progression in non-small cell lung cancer. Int J Mol Sci. 2016;17:437. 10.3390/ijms17040437

27023518

PMC4848893

119.

Huang

Ding

Wang

Transient receptor potential ion-channel subfamily V member 4: a potential target for cancer treatment. Cell Death Dis. 2019;10:497. 10.1038/s41419-019-1708-9

31235786

PMC6591233

120.

Wang

Zhang

Wang

Mao

Sun

TRPV4 overexpression promotes metastasis through epithelial-mesenchymal transition in gastric cancer and correlates with poor prognosis. Onco Targets Ther. 2020;13:8383–94. 10.2147/OTT.S256918

32943876

PMC7468412

121.

Liu

Zhang

Xie

Sham

KWY

SSM

Chen

Activation of PTEN by inhibition of TRPV4 suppresses colon cancer development. Cell Death Dis. 2019;10:460. 10.1038/s41419-019-1700-4

31189890

PMC6561944

122.

Yang

Liao

TRPV4 activates the Cdc42/N-wasp pathway to promote glioblastoma invasion by altering cellular protrusions. Sci Rep. 2020;10:14151. 10.1038/s41598-020-70822-4

32843668

PMC7447819