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

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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.