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Nitric oxide regulates cell sensitivity to cisplatin-induced apoptosis through S-nitrosylation and inhibition of Bcl-2 ubiquitination.

Authors
Chanvorachote-P; Nimmannit-U; Stehlik-C; Wang-LY; Jiang-BH; Ongpipatanakul-B; Rojanasakul-Y
Source
Cancer Res 2006 Jun; 66(12):6353-6360
NIOSHTIC No.
20030501
Abstract
Cisplatin is a potent cytotoxic agent commonly used for the treatment of solid tumors. However, tumor cell-acquired resistance to cisplatin-induced apoptosis is a major limitation for efficient therapy, as frequently observed in human lung cancer. Nitric oxide (NO) is a key regulator of apoptosis, but its role in cisplatin-induced cell death and the underlying mechanism are largely unknown. Previous studies indicate increased NO synthase activity and elevated NO production in lung carcinomas, which correlate with the incidence of chemotherapeutic resistance. Here, we show that NO impairs the apoptotic function of cells and increases their resistance to cisplatin-induced cell death in human lung carcinoma H-460 cells. The NO donors sodium nitroprusside and dipropylenetriamine NONOate were able to inhibit cisplatin-induced cell death, whereas the NO inhibitors aminoguanidine and 2-(4-carboxyphenyl)-4,4,5,5-tetra-methylimidazoline-1-oxyl-3-oxide had opposite effect. Cisplatin resistance in H-460 cells is mediated by Bcl-2, and NO up-regulates its expression by preventing the degradation of Bcl-2 via ubiquitin-proteasome pathway. Cisplatin-induced generation of reactive oxygen species causes dephosphorylation and degradation of Bcl-2. In contrast, generation of NO has no effect on Bcl-2 phosphorylation but induces S-nitrosylation of the protein, which inhibits its ubiquitination and subsequent proteasomal degradation. These findings indicate a novel pathway for NO regulation of Bcl-2, which provides a key mechanism for cisplatin resistance and its potential modulation for improved cancer chemotherapy.
Keywords
Oxides; Cytotoxins; Cytotoxicity; Cytotoxic-effects; Tumors; Lung-cancer; Cancer; Pulmonary-system-disorders; Carcinomas; Cell-function; Chemotherapy; Author Keywords: nitric oxide; cisplatin; apoptosis; Bcl-2; phosphorylation; ubiquitination
CODEN
CNREA8
CAS No.
10102-43-9; 15663-27-1
Publication Date
20060615
Document Type
Journal Article
Email Address
yrojanasakul@hsc.wvu.edu
Fiscal Year
2006
NTIS Accession No.
NTIS Price
Issue of Publication
12
ISSN
0008-5472
NIOSH Division
HELD
Priority Area
Work Environment and Workforce: Emerging Technologies
Source Name
Cancer Research
State
WV
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