TY  - JOUR
TI  - GDF11 induces chemosensitization in human hepatocellular carcinoma cells by decreasing drug-efflux transporters
AU  - German-Ramirez, Natanael
AU  - Gerardo-Ramírez, Monserrat
AU  - Domínguez-Gómez, Guadalupe I.
AU  - Masso-Rojas, Felipe
AU  - Paez-Arenas, Araceli
AU  - Perez-Aguilar, Benjamin
AU  - Bucio-Ortiz, Leticia
AU  - Souza-Arroyo, Veronica
AU  - Miranda-Labra, Roxana U.
AU  - Gutierrez-Ruiz, María Concepción
AU  - Simoni-Nieves, Arturo
AU  - Gomez-Quiroz, Luis E.
PY  - 2025
JO  - Exploration of Digestive Diseases
VL  - 4
SP  - 1005108
DO  - 10.37349/edd.2025.1005108
UR  - https://www.explorationpub.com/Journals/edd/Article/1005108
AB  - Aim: Hepatocellular carcinoma (HCC) accounts for 90% of liver tumors and is the fourth leading cause of cancer-related deaths worldwide. Current treatments have poor outcomes for HCC, highlighting the urgent need for new and effective therapies. Growth differentiation factor 11 (GDF11), a member of the TGF-β superfamily, regulates differentiation, proliferation, and migration processes, effects observed in cancer, including HCC. In this study, we aimed to investigate the chemosensitizing effects on human liver cancer cells. Methods: We pre-treated Huh7 and Hep3B cells with GDF11 50 ng/mL for 72 h in the presence of sorafenib (Sfb) or cisplatin (CDDP) and evaluated cellular response. Results: Pre-treatment with GDF11 lowered the IC50 of CDDP and Sfb in Huh7 cells. Similar effects were observed in Hep3B cells. Additionally, combining GDF11 with CDDP or Sfb significantly reduced cell viability and decreased the size and number of spheroids. Furthermore, we found that the chemosensitizing effect is initiated by GDF11 binding to the type I receptor ALK5. Inhibition of ALK5 abolished SMAD2 activation, impacting the chemosensitizing effects. Finally, GDF11, combined with Sfb or CDDP, reduced the activity of drug transporters MRP2, MRP3, and MRP4, which explains its chemosensitizing properties. Conclusions: GDF11 increases the sensitivity of HCC-derived cell lines to Sfb and CDDP by modulating the drug-efflux transporters MRP2, MRP3, and MRP4.
ER  -