Endothelial nitric oxide synthase uncoupling as a key mediator of melanocyte malignant transformation associated with sustained stress conditions

Author(s)

Melo, Fabiana H. M. ^[1] ; Molognoni, Fernanda ^{[2, 1]} ; Morais, Alice S. ^[2] ; Toricelli, Mariana ^[2] ; Mouro, Margareth G. ^[3] ; Higa, Elisa M. S. ^[3] ; Lopes, Jose D. ^[1] ; Jasiulionis, Miriam G. ^{[2, 1]}

Affiliation

^[1] Univ Fed Sao Paulo, Disciplina Imunol, BR-04023900 Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Disciplina Farmacol, BR-04023900 Sao Paulo - Brazil

^[3] Univ Fed Sao Paulo, Disciplina Nefrol, BR-04023900 Sao Paulo - Brazil

• Document type: Journal article
• Source: Free Radical Biology and Medicine; v. 50, n. 10, p. 1263-1273, MAY 15 2011.
• Web of Science Citations: 10

Abstract

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. (AU)

• FAPESP's process: 09/03335-8 - Identification of genes that present altered expression due to aberrant promoter methylation in the initial phases of melanoma progression
• Grantee: Alice Santana Morais
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 06/61293-1 - DNA methylation contribution to carcinogenesis
• Grantee: Miriam Galvonas Jasiulionis
• Support Opportunities: Research Grants - Young Investigators Grants