Apoptotic induction by simvastatin in human lung cancer A549 cells via Akt signaling dependent down-regulation of survivin.
Statins, HMG-CoA reductase inhibitors have been studied for their antiproliferative and proapototic effects. Recently, statin-induced apoptosis has been associated with down-regulation of survivin expression in cancer cells. However, the mechanism of deregulated survivin by simvastatin on lung cancer is still unclear. Herein, we demonstrated that simvastatin induced caspase-dependent apoptosis in A549 lung cancer cells. Simvastatin also resulted in a decrease in the expression of phosphorylated Akt. In addition, simvastatin effectively down-regulated survivin mRNA and protein, but not cIAP-1 and cIAP-2. The combination of simvastatin and 10 μM LY294002 (non-toxic dose) augmented apoptosis significantly, as evidenced by cleavage of PARP. The immunoreactive band of survivin was markedly decreased in cells treated with 50 μM LY294002 (toxic dose) as well as by the combination of simvastatin and 10 μM LY294002. Moreover, survivin down-regulation by RNA interference induced apoptosis accompanied by an increase in hypodiploid DNA content. Taken together, these data suggest that the anti-cancer effect of simvastatin via induction of apoptosis is related to Akt signaling dependent down-regulation of survivin in lung cancer A549 cells.
Hwang
Ki-Eun
KE
Department of Internal Medicine, Institute of Wonkwang Medical Science, School of Medicine, Wonkwang University, 344-2 shinyong-dong, Iksan, Jeonbuk 570-749, South Korea.
Na
Kyoung-Suk
KS
Park
Do-Sim
DS
Choi
Keum-Ha
KH
Kim
Byoung-Ryun
BR
Shim
Hyeok
H
Jeong
Eun-Taik
ET
Kim
Hak-Ryul
HR
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects; D000077022:Survivin
C107489:BIRC5 protein, human; D002867:Chromones; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D009025:Morpholines; D034741:RNA, Small Interfering; D000077022:Survivin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019821:Simvastatin; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases
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