Role of p21waf1/cip1 in effects of oxaliplatin in colorectal cancer cells.
Clinical studies have shown that oxaliplatin, a novel platinum derivative, is a potent chemotherapeutic agent for colorectal cancer when combined with 5-fluorouracil and leucovorin. Although the toxic activity is based on covalent adducts between platinum and DNA, its actual biological behavior is mostly unknown. In an effort to explore the mechanism of tumor susceptibility to oxaliplatin, we examined the cytotoxic effects of oxaliplatin in colorectal cancer cell lines in reference to p53 gene status. Although p53 gene status did not clearly predict sensitivity to oxaliplatin, p53 wild-type cells including HCT116 were sensitive but HCT116 p53-/- were found to be resistant to oxaliplatin. Oxaliplatin caused strong p21waf1/cip1 induction and G0-G1 arrest in p53 wild-type cells, whereas cisplatin did not induce G0-G1 arrest. Assays using p53 wild but p21waf1/cip1 null HCT116 cells revealed that oxaliplatin did not show G0-G1 arrest and reduced growth-inhibitory effects, suggesting that p21waf1/cip1 may be a key element in oxaliplatin-treated p53 wild-type cells. Although HCT116 is DNA mismatch repair-deficient, a mismatch repair-proficient HCT116+ch3 cell line displayed similar responses with regard to p21waf1/cip1-mediated growth inhibition and G0-G1 arrest. In p53 mutant cells, on the other hand, oxaliplatin caused an abrupt transition from G1 to S phase and eventually resulted in G2-M arrest. This abrupt entry into S phase was associated with loss of the p21waf1/cip1 protein via proteasome-mediated degradation. These findings suggest that p21waf1/cip1 plays a role in oxaliplatin-mediated cell cycle and growth control in p53-dependent and -independent pathways.
Hata
Taishi
T
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan.
Yamamoto
Hirofumi
H
Ngan
Chew Yee
CY
Koi
Minoru
M
Takagi
Akimitsu
A
Damdinsuren
Bazarragchaa
B
Yasui
Masayoshi
M
Fujie
Yujiro
Y
Matsuzaki
Takeshi
T
Hemmi
Hiromichi
H
Xu
Xundi
X
Kitani
Kotaro
K
Seki
Yosuke
Y
Takemasa
Ichiro
I
Ikeda
Masataka
M
Sekimoto
Mitsugu
M
Matsuura
Nariaki
N
Monden
Morito
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology*; D004260:DNA Repair; D016158:Genes, p53 / Q000235:genetics / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009154:Mutation; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; D000077150:Oxaliplatin