SarCNU-induced G2/M arrest in hepatoma cells is mediated by a p53-independent phosphorylation of cdc-2 at Tyr15.
Hepatocellular carcinoma (HCC) is a major health problem in the Asia-Pacific region, with high incidence and mortality rate. There is currently no effective treatment for inoperable cases that represent the vast majority of patients. In the present study, we report that in vitro treatment of primary hepatoma, HepG2 (wild-type p53), PLC/PRF/5 (p53-mutant), and Hep3B (p53-deleted) cells with 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) resulted in upregulation of p53, p21(Cip1/Waf1), phosphorylated cdc-2 at Tyr15 in wild-type p53 cells and phosphorylation of cdc-2 at Tyr15 in p53-mutant or p53-deleted hepatoma cells. This was accompanied by the reduction in cdc-2 kinase activity and G(2)/M cell cycle arrest. These findings indicate that SarCNU-induced G(2)/M growth arrest in hepatoma cells by a p53-independent phosphorylation of cdc-2. Our data suggest the potential use of SarCNU in treatment of HCC.
Hung
Huynh
H
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore. cmrhth@nccs.com.sg
Pierce
Chow Kad Hoe
CK
Chee
Soo Khee
SK
Lawrence
Panasci
P
Hung
Nguyen Thanh
NT
D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002330:Carmustine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008938:Mitosis / Q000187:drug effects*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D019000:Phosphotyrosine; C044565:2-((((2-chloroethyl)nitrosoamino)carbonyl)amino)propanamide; D016203:CDC2 Protein Kinase; D002330:Carmustine