Banca de DEFESA: LETÍCIA SILVA FERRAZ

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
DISCENTE : LETÍCIA SILVA FERRAZ
DATA : 15/12/2020
HORA: 14:00
LOCAL: Santo André
TÍTULO:

MODULATION OF THE MAPK/ERK PATHWAY BY VEMURAFENIB AND ITS IMPACTS ON MITOCHONDRIAL DYNAMICS IN MELANOMA

PÁGINAS: 123
GRANDE ÁREA: Ciências Biológicas
ÁREA: Bioquímica
SUBÁREA: Metabolismo e Bioenergética
RESUMO:

Melanoma is a proliferative malignant disease originating in melanocytes, characterized by high metastatic activity and mortality and the presence of oncogenes, such as BRAF (40 - 50% and NRAS (15 - 20%). Vemurafenib is an inhibitor of the MAPK pathway that prolongs the survival of patients with non-operable metastatic melanoma or B-RAF^V600Emutation. Recent studies suggest mitochondria as the target of action of vemurafenib, however, the underlying mechanisms are not entirely clear. Mitochondria are highly dynamic organelles that constantly fuse and divide, contributing to the mitochondrial network adapting to changes in the metabolic needs of cells, GTPases related to dinamine, MFN1, MFN2 and OPA1, are necessary for mitochondrial fusion, while DRP1 is necessary for fission. The aim of this study was to characterize the changes in mitochondrial dynamics caused by vemurafenib in mutated B-RAF and N-RAS melanoma cell lines. The inhibition of MAPK by vemurafenib in the SK-MEL-19 (B-RAF^V600E) cells culminated in the inhibition of DRP1 phosphorylation, associated with a major remodeling of the mitochondrial network to the hyperfused phenotype and an increase in the oxidative phosphorylation capacity. Such changes may be associated with melanoma resistance to vemurafenib, since the impairment of oxidative phosphorylation increased the cytotoxicity of vemurafenib. In contrast, in the SK-MEL-147 (N-RAS^Q61R) cells, in which vemurafenib causes paradoxical activation of the MAPK pathway, we observed changes in functional parameters of the mitochondria without inducing cell death, which was altered with the addition of respiratory chain inhibitors or inhibitor DRP1, sensitizing them to cell death induced by vemurafenib. These results point to the potential of mitochondrial dynamics as a possible therapeutic target in melanoma.

MEMBROS DA BANCA:
Presidente - Interno ao Programa - 1674592 - TIAGO RODRIGUES
Membro Titular - Examinador(a) Interno ao Programa - 2605490 - SERGIO DAISHI SASAKI
Membro Titular - Examinador(a) Externo à Instituição - SERGIO AKIRA UYEMURA
Membro Titular - Examinador(a) Externo à Instituição - MIRIAM GALVONAS JASIULIONIS - UNIFESP
Membro Titular - Examinador(a) Externo à Instituição - ROGER FRIGERIO CASTILHO - UNICAMP
Membro Suplente - Examinador(a) Interno ao Programa - 1653932 - MARCELO AUGUSTO CHRISTOFFOLETE
Membro Suplente - Examinador(a) Interno ao Programa - 2353139 - ELOAH RABELLO SUAREZ
Membro Suplente - Examinador(a) Externo à Instituição - GILBERTO EIJI SHIGUEMOTO - UFSCAR
Membro Suplente - Examinador(a) Externo à Instituição - DENISE COSTA ARRUDA - UMC