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

• Grant number: 19/14722-4
• Support Opportunities: Regular Research Grants
• Duration: February 01, 2020 - July 31, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Gustavo José da Silva Pereira
• Grantee: Gustavo José da Silva Pereira
• Host Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PEREIRA, GUSTAVO JOSE DA SILVA; LEAO, ANDERSON HENRIQUE FRANCA FIGUEREDO; ERUSTES, ADOLFO GARCIA; MORAIS, INGRID BEATRIZ DE MELO; VRECHI, TALITA APARECIDA DE MORAES; ZAMARIOLI, LUCAS DOS SANTOS; PEREIRA, CASSIA ARRUDA SOUZA; MARCHIORO, LAIS DE OLIVEIRA; SPERANDIO, LETICIA PAULINO; LINS, ISIS VALESKA FREIRE; et al. Pharmacological Modulators of Autophagy as a Potential Strategy for the Treatment of COVID-19. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 8, APR 2021. (19/14722-4, 17/10863-7, 19/02821-8)

VRECHI, TALITA A. M.; LEAO, ANDERSON H. F. F.; MORAIS, INGRID B. M.; ABILIO, VANESSA C.; ZUARDI, ANTONIO W.; HALLAK, JAIME EDUARDO C.; CRIPPA, JOSE ALEXANDRE; BINCOLETTO, CLAUDIA; URESHINO, RODRIGO P.; SMAILI, SORAYA S.; et al. Cannabidiol induces autophagy via ERK1/2 activation in neural cells. SCIENTIFIC REPORTS, v. 11, n. 1, MAR 8 2021. (18/06260-8, 19/02821-8, 19/14722-4, 17/10863-7, 16/20796-2)

ERUSTES, ADOLFO GARCIA; D'ELETTO, MANUELA; GUARACHE, GABRIEL CICOLIN; URESHINO, RODRIGO PORTES; BINCOLETTO, CLAUDIA; DA SILVA PEREIRA, GUSTAVO JOSE; PIACENTINI, MAURO; SMAILI, SORAYA SOUBHI. Overexpression of alpha-synuclein inhibits mitochondrial Ca2+ trafficking between the endoplasmic reticulum and mitochondria through MAMs by altering the GRP75-IP3R interaction. Journal of Neuroscience Research, v. 99, n. 11, SEP 2021. (19/02821-8, 16/05580-3, 17/10863-7, 13/20073-2, 19/14722-4, 16/20796-2)