Dr. Zui Pan E-Mail
College of Nursing and Health Innovation, The University of Texas at Arlington, TX, USA
Research Keywords: esophageal cancer; calcium signaling; store-operated calcium entry; live cell imaging; chemotherapy
intracellular Ca2+ signaling is associated with the development of
malignant phenotypes. Cancer cells remodel their Ca2+ signaling
apparatus to enhance proliferation, to increase cell motility and
invasion, to resist apoptosis, to escape from immune-attack, or to have
neovascularization. There has been an increasing awareness that
tumorigenic pathways are associated with altered expression or abnormal
activation of Ca2+ channels, transporters or Ca2+-pumps. Targeting the
altered Ca2+ signaling apparatus to develop new anti-cancer drugs is
emerging, yet many challenges remains. Intracellular Ca2+ homeostasis
plays important role in normal physiology and cell functions; thus, it
is important to identify the cancer specific properties of the Ca2+ apparatus. Different cancers or different stages during tumor
development may present distinct different alteration in Ca2+ signaling
apparatus. More specific, more potent and less off-target compounds
targeting Ca2+ channels/transporters/pumps are urgently needed.
This special issue will highlight the current state of diverse molecular mechanisms of intracellular Ca2+ involved in cell proliferation, apoptosis, migration, invasion, or angiogenesis in different cancers. It will also discuss developing effective novel cancer treatment targeting Ca2+ channels, transporters or Ca2+-pumps.
Keywords: calcium channels; cell proliferation; apoptosis; migration; metastasis; transcription factors; chemotherapy
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.
Metastasis is still the primary cause of cancer-related mortality. However, the underlying mechanisms of cancer metastasis are not yet fully understood. Currently, the epithelial-mesenchymal transition, metabolic remodeling, cancer cell intercommunication and the tumor microenvironment including diverse stromal cells, are reported to affect the metastatic process of cancer cells. Calcium ions (Ca2+) are ubiquitous second messengers that manipulate cancer metastasis by affecting signaling pathways. Diverse transporter/pump/channel-mediated Ca2+ currents form Ca2+ oscillations that can be decoded by Ca2+-binding proteins, which are promising prognostic biomarkers and therapeutic targets of cancer metastasis. This paper presents a review of the advances in research on the mechanisms underlying cancer metastasis and the roles of Ca2+-related signals in these events.
Intracellular Ca2+ ions that are thought to be one of the most important second messengers for cellular signaling, have a substantial diversity of roles in regulating a plethora of fundamental cellular physiology such as gene expression, cell division, cell motility and apoptosis. It has been suggestive of the Ca2+ signaling-dependent cellular processes to be tightly regulated by the numerous types of Ca2+ channels, pumps, exchangers and sensing receptors. Consequently, dysregulated Ca2+ homeostasis leads to a series of events connected to elevated malignant phenotypes including uncontrolled proliferation, migration, invasion and metastasis, all of which are frequently observed in advanced stage lung cancer cells. The incidence of bone metastasis in patients with advanced stage lung cancer is estimated in a range of 30% to 40%, bringing about a significant negative impact on both morbidity and survival. This review dissects and summarizes the important roles of Ca2+ signaling transduction in contributing to lung cancer progression, and address the question: if and how Ca2+ signaling might have been engaged in metastatic lung cancer with bone metastasis, thereby potentially providing the multifaceted and promising solutions for therapeutic intervention.
Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with high heterogeneity, rapid progression, and paucity of treatment options. The most effective chemotherapeutic drug used to treat TNBC is doxorubicin (Doxo) which is an anthracycline antibiotic. However, Doxo treatment alters cytosolic calcium dynamics leading to drug-resistance condition. The aim of this study is to capture the alterations in the activity of various calcium channels and pumps during Doxo treatment and their consequences on cytosolic calcium dynamics that ultimately result in drug resistance.
In the present study, a mathematical model is proposed to capture the complex dynamical landscape of intracellular calcium during Doxo treatment. This study provides an insight into Doxo remodeling of calcium dynamics and associated drug-resistance effect. The model was first analyzed analytically and then explored through numerical simulation using techniques like global sensitivity analysis, parameter recalibration, etc.
The model is used to predict the potential combination therapy for Doxo that can overcome Doxo associated drug resistance. The results show targeting the dysregulated Ca2+ channels and pumps might provide efficient chemotherapy in TNBC. It was also observed that the indispensability of calcium influx rate is paramount in the Doxo drug resistance. Finally, three drugs were identified from existing literature that could be used as a combination therapy along with Doxo.
The investigation highlights the importance of integrating the calcium signaling of various calcium regulating compounds for their effective anti-tumor effects deliverance along with chemotherapeutic agents. The results from this study might provide a new direction to the experimental biologists to explore different combination therapies with Doxo to enhance its anti-tumor effect.