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.
Highlights
The cell cycle in eukaryotes is controlled, at least in part, by a family of protein kinase complexes wherein each complex is composed of a catalytic subunit, the cyclin-dependent kinase (CDK), and its essential regulatory subunit, the cyclins
The cyclinCDK complexes are subject to inhibition via binding to a class of proteins known as the CDK inhibitors, such as p21 (WAF/CIP1), resulting in blockade of cell cycle progression. p21CIP1 is able to bind proliferating cell nuclear antigen (PCNA) as well as CDK, thereby inhibiting the cell cycle progression
SC-560 effect in HCT116/WT cells When we treated HCT116/WT (p21+/+) cells with increasing doses of SC-560 for 48 h, we found that SC-560 dose-dependently inhibited the growth of HCT116 cells (Figure 1A)
Summary
The cell cycle in eukaryotes is controlled, at least in part, by a family of protein kinase complexes wherein each complex is composed of a catalytic subunit, the cyclin-dependent kinase (CDK), and its essential regulatory subunit, the cyclins. By using p21+/+ and p21-/- isogenic HCT116 cell lines, we show here that p21CIP1 is not crucial in SC-560-induced G1-phase arrest, but it plays an important role in protecting cells from apoptotic cell death subsequent to SC-560 treatment. SC-560 effect in HCT116/WT cells When we treated HCT116/WT (p21+/+) cells with increasing doses of SC-560 for 48 h, we found that SC-560 dose-dependently inhibited the growth of HCT116 cells (Figure 1A).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
