Role of p21CIP1 as a determinant of SC-560 response in human HCT116 colon carcinoma cells.

Abstract

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.

• Authors: Eunmyong Lee, Moon Kyung Choi, Inn Oc Han, Soo Jeong Lim
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 38 Issue 3 Pg. 325-31 (Jun 30 2006) ISSN: 1226-3613 [Print] United States
• PMID: 16819292 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• CDKN1A protein, human
• Cell Cycle Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclooxygenase Inhibitors
• Pyrazoles
• Reactive Oxygen Species
• SC 560

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Differentiation (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Colonic Neoplasms (genetics, metabolism, pathology)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism, physiology)
• Cyclooxygenase Inhibitors (pharmacology)
• Dose-Response Relationship, Drug
• Flow Cytometry
• Genotype
• HCT116 Cells
• Humans
• Immunoblotting
• Mutation
• Pyrazoles (pharmacology)
• Reactive Oxygen Species (metabolism)