Role of p21CIP1 as a determinant of SC-560 response in human HCT116 colon carcinoma cells.
SC-560, a structural analogue of celecoxib, induces growth inhibition in a wide range of human cancer cells in a cyclooxygenase (COX)-independent manner. Since SC-560 suppresses the growth of cancer cells mainly by inducing cell cycle arrest, we sought to examine the role of p21CIP1, a cell cycle regulator protein, in the cellular response against SC-560 by using p21(+/+) and p21(-/-) isogenic HCT116 colon carcinoma cells. In HCT116 (p21(+/+)) cells, SC-560 dose-dependently induced growth inhibition and cell cycle arrest at the G1 phase without significant apoptosis induction. SC-560-induced cell cycle arrest was accompanied by upregulation of p21CIP1. However, the extent of SC-560-induced accumulation at the G1 phase was approximately equal in the p21(+/+) and the p21(-/-) cells. Nonetheless, the growth inhibition by SC-560 was increased in p21(-/-) cells than p21(+/+)cells. SC-560-induced reactive oxygen species (ROS) generation did not differ between p21(+/+) and p21(-/-) cells but the subsequent activation of apoptotic caspase cascade was more pronounced in p21(-/-) cells compared with p21(+/+) cells. These results suggest that p21CIP1 blocks the SC-560-induced apoptotic response of HCT116 cells. SC-560 combined with other therapy that can block p21 CIP1 expression or function may contribute to the effective treatment of colon cancer.
Lee
Eunmyong
E
Department of Bioscience and Biotechnology, Sejong University, Seoul 143-747, Korea.
Choi
Moon Kyung
MK
Han
Inn Oc
IO
Lim
Soo Jeong
SJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005838:Genotype; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D009154:Mutation; D011720:Pyrazoles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D017382:Reactive Oxygen Species; C115461:SC 560