Endothelial nitric oxide synthase uncoupling as a key mediator of melanocyte malignant transformation associated with sustained stress conditions
Nenhuma Miniatura disponível
Arquivos
Data
2011-05-15
Autores
Melo, Fabiana Henriques Machado de [UNIFESP]
Molognoni, Fernanda [UNIFESP]
Morais, Alice Santana [UNIFESP]
Toricelli, Mariana [UNIFESP]
Mouro, Margaret Gori [UNIFESP]
Higa, Elisa Mieko Suemitsu [UNIFESP]
Lopes, Jose Daniel [UNIFESP]
Jasiulionis, Miriam Galvonas [UNIFESP]
Orientadores
Tipo
Artigo
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Melanoma cell lines and cells corresponding to premalignant melanocytes were established by our group after subjecting a nontumorigenic murine melanocyte lineage, melan-a, to sequential cycles of anchorage blockade. Previous results showed that in melan-a cells the superoxide level increases after such procedure. Superoxide production during melanocyte de-adhesion was inhibited by L-sepiapterin, the precursor of eNOS cofactor BH(4), and increased by the inhibitor of BH(4) synthesis, DAHP, hence indicating a partial uncoupling state of eNOS. the eNOS uncoupling seems to be maintained in cells derived from melan-a, because they present decreased nitric oxide and increased superoxide levels. the inhibition of superoxide production in Tm5 melanoma cells with L-sepiapterin reinforces their eNOS-uncoupled state. the maintenance of oxidative stress seems to be important in melanoma apoptosis resistance because Mn(III)TBAP, a superoxide scavenger, or L-sepiapterin renders Tm5 cells more sensitive to anoikis and chemotherapy. More importantly, eNOS uncoupling seems to play a pivotal role in melanocyte malignant transformation induced by sustained anchorage impediment, because no malignant transformation was observed when L-NAME-treated melanocytes were subjected to sequential cycles of de-adhesion. Our results show that uncoupled eNOS contributes to superoxide production during melanocyte anchorage impediment, contributing to anoikis resistance and malignant transformation. (C) 2011 Elsevier Inc. All rights reserved.
Descrição
Citação
Free Radical Biology and Medicine. New York: Elsevier B.V., v. 50, n. 10, p. 1263-1273, 2011.