Cell cycle arrest and apoptotic induction in LNCaP cells by MCS-C2, novel cyclin-dependent kinase inhibitor, through p53/p21WAF1/CIP1 pathway.
The purpose of the present study was to investigate the mechanisms involved in the antiproliferative and apoptotic effects of MCS-C2, a novel analog of the pyrrolo[2,3-d]pyrimidine nucleoside toyocamycin and sangivamycin, in human prostate cancer LNCaP cells. MCS-C2, a selective inhibitor of cyclin-dependent kinase, was found to inhibit cell growth in a time- and dose-dependent manner, and inhibit cell cycle progression by inducing the arrest of the G1 phase and apoptosis in LNCaP cells. When treated with 3 microM MCS-C2, inhibited proliferation associated with apoptotic induction was found in the LNCaP cells in a concentration and time-dependent manner, and nuclear DAPI staining revealed the typical nuclear features of apoptosis. Furthermore, MCS-C2 induced cell cycle arrest in the G1 phase through the upregulated phosphorylation of the p53 protein at Ser-15 and activation of its downstream target gene p21WAF1/CIP1. Accordingly, these results suggest that MCS-C2 inhibits the proliferation of LNCaP cells by way of G1-phase arrest and apoptosis in association with the regulation of multiple molecules in the cell cycle progression.
Park
Hae Young
HY
Department of Urology, Hanyang University College of Medicine, Seoul 133-791, Korea.
Kim
Min Kyoung
MK
Moon
Sang-Ik
SI
Cho
Youl-Hee
YH
Lee
Chul-Hoon
CH
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014127:Toyocamycin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C502156:MCS-C2; D016159:Tumor Suppressor Protein p53; D012694:Serine; D018844:Cyclin-Dependent Kinases; D014127:Toyocamycin