p53-R175H mutant gains new function in regulation of doxorubicin-induced apoptosis

Abstract

Mutation of tumor suppressor p53 gene gains new function in regulation of DNA damage-induced apoptotic response in tumor cells, which may lead to a poor response in cancer chemotherapy and radiotherapy. Transfection of mutant p53 (R175H) to p53-null osteosarcoma Saos-2 cells suppressed apoptosis induced by doxorubicin (DOX), cisplatin and gamma radiation. Downregulation of caspase-3 but not -8 or -9 basal protein levels was also observed in Saos-2 cells transfected with p53-R175H. After 48 hr of DOX treatment, the rate of procasapse-3 activation into 17 kDa active form was about 3-fold higher in the control cells than that in the p53-R175H counterpart. Gene silencing of p53-R175H expression by p53 siRNA upregulate the procaspase-3 protein level and restored DOX-induced apoptosis in p53-R175H cells. Our results suggest that p53-R175H mutation may gain new function in decreasing DOX-induced apoptotic response through suppression of caspase-3 level and its activation. © 2005 Wiley-Liss, Inc.