Requirement for pre-existing of p21 to prevent doxorubicin-induced apoptosis through inhibition of caspase-3 activation.
Doxorubicin (DOX)-induced apoptosis is suppressed by p21 (waf1/cip1/sdi1), a cyclin dependent kinase (CDK) inhibitor. Here we show that exogenous expression of p21 before, but not after, the DOX-treatment protected p21-deficient human colorectal cancer cell line DLD1 from DOX-induced apoptosis. In previous work, we demonstrated that p21 inhibits DOX-induced apoptosis via its CDK-binding and CDK-inhibitory activity. Here we report that pre-existing p21 can associate with pro-caspase-3 and inhibit caspase-3 activation in the cells, which was at least in part responsible for enhancing survival of DOX-treated cells. Furthermore, the N-terminal domain of p21 was found to interact with pro-caspase-3 in DLD1 cells. Thus, we propose that pre-existing p21 is required to prevent DOX-induced apoptosis.
Tang
J J
JJ
Cancer Research Center, Celstar Bio-Pharmaceutical Co. Ltd., Shanghai, PR China.
Shen
C
C
Lu
Y J
YJ
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D017434:Protein Structure, Tertiary
D000903:Antibiotics, Antineoplastic; D061945:Caspase Inhibitors; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004317:Doxorubicin