Wnt-1 signaling inhibits apoptosis by activating beta-catenin/T cell factor-mediated transcription

Wnt signaling plays a critical role in development and oncogenesis. Althoug h significant progress has been made in understanding the downstream signal ing cascade of Wnt signaling, little is known regarding Wnt signaling modif ication of the cell death machinery, Given that numerous oncogenes transfor m cells by providing cell survival function, we hypothesized that Wnt signa ling may inhibit apoptosis. Here, we report that cells expressing Wnt-l wer e resistant to cancer therapy-mediated apoptosis. Wnt-l signaling inhibited the cytochrome c release and the subsequent caspase-9 activation induced b y chemotherapeutic drugs, including both vincristine and vinblastine, Furth ermore, wefound that Wnt-1-mediated cell survival was dependent on the acti vation of beta -catenin/T cell factor (Tcf) transcription. Inhibition of be ta -catenin/Tcf transcription by expression of the dominant-negative mutant of Tcf-4 blocked Wnt-1-mediated cell survival and rendered cells sensitive to apoptotic stimuli. These results provide the first demonstration that W nt-1 inhibits cancer therapy-mediated apoptosis and suggests that Wnt-1 may exhibit its oncogenic potential through a mechanism of anti-apoptosis.