Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 50, Issue 10, Pages 1263-1273Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2011.02.022
Keywords
eNOS uncoupling; Superoxide anion; Melanocytes; Anoikis; Malignant transformation; Free radicals
Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [06/61293-1, 05/60334-3, 08/50366, 09/03335-8]
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [06/61293-1, 09/03335-8] Funding Source: FAPESP
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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.
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