Induction of apoptosis and G2/M arrest by N-methyl-N'-nitro-N-nitrosoguanidine in human prostate carcinoma cells.
We have investigated the effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a well known DNA alkylating agent, on the growth and cell cycle progression in human prostate carcinoma PC-3 and DU145 cells, which are lacking both p53 alleles and having mutated p53, respectively. It was found that MNNG could inhibit the cell growth in a dose-dependent manner, which was associated with dendrite-like morphological change and induction of apoptotic cell death. Flow cytometry showed that MNNG could cause an arrest at the G2/M phase of the cell cycle, which is closely correlated to inhibition of cyclin-dependent kinase (Cdk) 2 and Cdc2 kinase activities. Furthermore, this compound induced Cdk inhibitor p21WAF1/CIP1 expression at both the transcription and protein levels in a p53-independent manner. MNNG also activated the reporter construct of a p21 promoter. Present results indicate that the up-regulation of p21 by MNNG is likely responsible for the inhibition of Cdks kinase activity rather than the down-regulation of cyclins and Cdks expression.
Park
Cheol
C
Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan 614-052, Republic of Korea.
Choi
Byung Tae
BT
Cheong
JaeHun
J
Moon
Sung-Kwon
SK
Kim
Cheorl-Ho
CH
Lee
Won Ho
WH
Choi
Yung Hyun
YH
D017209:Apoptosis / Q000187:drug effects*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D008769:Methylnitronitrosoguanidine; D016203:CDC2 Protein Kinase