Two-Pore Channels receptors and TFEB-3 autophagy modulation in human hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a primary liver neoplasm that originates in hepatocytes caused by hepatitis B and C virus infections, which are the major etiologic causes of HCC, either through carcinogenesis or cirrhosis. Most of the patients undergoing therapy have the option of treatment with sorafenib, a drug-target multi-kinase inhibitor treatment; however, drug resistance is still common in many patients. This is a complex phenomenon and the adaptive mechanisms are not yet fully elucidated. One of the key pathways in response to nutrient deprivation and chemotherapeutic action is the translocation to the nucleus of TFEB and TFE3 (TFEB/3) transcription factors that potentiate autophagy and lysosomal biogenesis, being recently considered as oncogenes. Our laboratory has shown in several cell models that Two-Pore Channels (TPCs)-mediated Ca2+ signaling induces autophagy, but its role in cancer has not yet been explored. Here we will investigate the role of TFEB/3 using HCC lines treated by selective TPC receptor agonists/antagonists and investigate how Ca2+ signal transduction mechanisms mediated by TPCs on TFEB/3 autophagy modulation may affect proliferation, migration, invasion and chemosensitization processes in HepG2 and HuH-7 cells. For this purpose, proteomic, biochemical and molecular biology methodologies will be used to study the autophagic pathways mediated by TFEB/3 and target genes in response to different treatments that induce the nuclear translocation of these transcription factors. The results will provide new drug targets that potentially play a key role in cancer treatment. (AU)