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

Abstract

SC-560, a strucutral 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 activaton 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.