Down-regulation of survivin in nitric oxide-induced cell growth inhibition and apoptosis of the human lung carcinoma cells.
Survivin is expressed in most tumor cells and has been associated with both anti-apoptosis and mitotic progression. However, the mechanism of regulation of the survivin expression remains unclear. In this study we investigated the expression and regulation of survivin in the nitric oxide (NO)-exposed human lung carcinoma cells. The lung carcinoma cell lines CL3, H1299, and A549 but not normal lung fibroblast expressed high levels of survivin proteins. NO donors S-nitroso-N-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) decreased the survivin expression. SNAP (0.4 mm, 24h)and SNP (1 mm, 24 h) significantly induced cytotoxicity and apoptosis in lung carcinoma cells. Furthermore, SNAP inhibited the cell growth and increased the fractions of G(2)/M phase. The levels of cyclin B1 and phospho-cdc2-(Thr-161) proteins were inhibited in the NO-exposed cells. The cdc25 phosphatase inhibitors (Cpd 5 and NSC 663284) and the cdc2 kinase inhibitors (alsterpaullone and purvalanol A) enhanced SNP-induced cytotoxicity and the decrease in survivin expression. However, overexpression of survivin by a pOTB7-survivin vector reduced SNP-induced cell growth inhibition and cytotoxicity. In addition, SNP activated the phosphorylation of p38 mitogen-activated protein (MAP) kinase. The specific p38 MAP kinase inhibitor, SB202190, significantly decreased the cytotoxicity and increased the survivin levels in NO donor-treated and inducible NOS-transfected cells. Conversely, anticancer agents including quercetin, arsenite, and cisplatin but not genistein increased the levels of survivin protein. Our results indicated for the first time that NO inhibited the expression of survivin, which was down-regulated by the p38 MAP kinase pathway.
Chao
Jui-I
JI
Molecular Toxicology Laboratory, Institute of Pharmacology and Toxicology, College of Life Sciences, Tzu Chi University, 701 Section 3 Chung-Yang Road, Hualien 970, Taiwan. chaoji@mail.tcu.edu.tw
Kuo
Pao-Chen
PC
Hsu
Tzu-Sheng
TS
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D018053:Arsenites / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D002277:Carcinoma / Q000473:pathology*; D002453:Cell Cycle; D002455:Cell Division; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019084:Fluorescent Antibody Technique, Indirect; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008938:Mitosis; D009363:Neoplasm Proteins; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
C471843:6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine; D000970:Antineoplastic Agents; D018053:Arsenites; C107489:BIRC5 protein, human; D001552:Benzazepines; D007093:Imidazoles; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; C440614:NSC 663284; D009363:Neoplasm Proteins; D011687:Purines; D011725:Pyridines; D015363:Quinolones; D011809:Quinones; C110881:S-nitro-N-acetylpenicillamine; D000077022:Survivin; C120793:alsterpaullone; D009599:Nitroprusside; D009569:Nitric Oxide; D011794:Quercetin; D016203:CDC2 Protein Kinase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010396:Penicillamine; C015001:arsenite; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D002945:Cisplatin