A p53 and apoptotic independent role for p21(waf1) in tumour response to radiation therapy

Loss of p21 in human cancer cells results in checkpoint failure, induction of polyploidy and subsequent apoptosis following DNA damage. Tumours in imm unodeficient mice derived from cells lacking p21 are also more sensitive to ionizing radiation than their wild-type counterparts. Abrogation of p53 in the p21(+/+) parental cells results in an in vitro phenotype that is indis tinguishable from that of the p21 knockout cells. Thus, the in vitro phenot ype resulting from loss of p21 is consistent with its well-established role in the p53/p21 damage response pathway. However, despite the similar in vi tro phenotype, p21(+/+) cells with abrogated p53 show no evidence of the se nsitivity observed in the p21(-/-) cells when grown as tumours in immunodef icient mice. The increased radio-sensitization stabilization of p21(-/-) tu mours is also unrelated to the increase in apoptosis observed in these tumo urs following radiation treatment. Apoptosis in the p21(-/-) tumours was si gnificantly reduced by expression of bcl-2 without any corresponding change in the overall response of the tumour. Similarly, abrogation of p53 in the p21(+/+) tumours substantially increased radiation-induced apoptosis withi n the tumours without increasing their radiation sensitivity. Dissociation of these in vivo and in vitro phenotypes indicates that p21 participates in a novel in vivo specific damage response pathway that is distinct from its role in the p53 pathway, and therefore that it may be an effective therape utic target for cancer therapy.