p53 promotes selection for Fas-mediated apoptotic resistance

Although p53 inactivation is implicated as a mechanism to explain diminishe d apoptotic response, it is clear that tumor cells that possess transcripti onally functional p53 can also be resistant to diverse apoptotic stimuli, W e hypothesize that oncogenic activation and DNA damage are sufficient stimu li to increase the p53-dependent transcription of Fas and thereby establish a situation in which cell to cell contact could be a selective pressure to either lose p53 function or inactivate components of the Fas death pathway . Examination of genetically matched tumor cell lines that possessed either wild-type or null p53 loci indicated that cells possessing functional p53 increased their surface levels of Fas and Fas ligand (FasL) in response to DNA damage. In contrast, stress induced by changes in the tumor microenviro nment such as decreased oxygen did not up-regulate Fas or Fast. Cells with wild-type p53 underwent Fas-mediated killing in the presence of either Fast -expressing killer cells or activating Fas antibodies, whereas cells in whi ch p53 was deleted or inactivated were protected from such killing. Further more, Fas and Fast expression and induction became transcriptionally repres sed in transformed cells with wild-type p53 with increasing passage, wherea s other p53 downstream targets and functions, such as p21 inducibility and cell cycle arrest, remained intact. Repression of the Fas Locus could be re verted by treatment with the histone deacetylase inhibitor trichostatin A. These results support a model of tumor progression in which oncogenic trans formation drives tumor cells to lose either p53 or their Fas sensitivity as a means of promoting their survival and evade immune surveillance.