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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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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]
Total Authors: 8
[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
Total Affiliations: 3
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

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