Lovastatin-induced E2F-1 modulation and its effect on prostate cancer cell death.
Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, induces growth arrest in a variety of cancer cell lines. Its mechanism of action, however, has not been completely elucidated. E2F-1 is thought to act as an oncogene and a tumour suppressor, with its action probably dependent upon the cellular context. We have shown in this study that transcriptional regulation and proteasomal degradation of E2F-1 are critical regulatory events in lovastatin-induced cell death. Accompanying this is a reduction in the E2F-1-regulated expression of cell cycle genes such as c-myc, cyclin D1, cyclin A and cyclin B1. Cell cycle analysis demonstrated that the accumulation of apoptotic cells was preceded by a progressive decrease in the S-phase cell population in response to lovastatin. Although expression of E2F-1 was reduced in three prostate cancer cell lines-PC-3, LNCaP and DU-145-the p21 and p27 protein levels were not increased in all the cell lines treated, suggesting that increase in p21 and p27 protein expression per se is not responsible for lovastatin-mediated down-regulation of E2F-1. The subsequent apoptotic death of these cells in the presence of lovastatin can be prevented by forced ectopic expression of E2F-1. Taken together, these facts imply that E2F-1 is the target of an HMG-CoA inhibitor and critical cell death mediator in prostate cancer cells.
Park
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Department of Medicine and Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul, Korea.
Lee
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Kang
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WK
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002154:Calpain / Q000037:antagonists & inhibitors; D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009842:Oligopeptides; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C069861:calpain inhibitor 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D002154:Calpain