Transforming growth factor β induces apoptosis through repressing the phosphoinositide 3-kinase/AKT/survivin pathway in colon cancer cells

FET cells, derived from an early-stage colon carcinoma, are nontumorigenic in athymic mice. Stable transfection of a dominant-negative transforming growth factor beta (TGF beta) type II receptor (DNRII) into FET cells that express autocrine TGF beta shows loss of TGF beta signaling and increased tumorigenicity in vivo indicating tumor suppressor activity of TGF beta signaling in this model. The ability of tumorigenic cells to withstand growth factor and nutrient deprivation stress (GFDS) is widely regarded as a key attribute for tumor formation and progression. We hypothesized that increased tumorigenicity of FET/DNRII cells was due to loss of participation of autocrine TGF beta in a fail-safe mechanism to generate cell death in response to this stress. Here, we document that loss of autocrine TGF beta in FET/DNRII cells resulted in greater endogenous cell survival in response to GFDS due to activation of the phosphoinositide 3-kinase (PI3K)/Akt/survivin pathway. Treatment of FET DNRII cells with a PI3K inhibitor (LY294002) inhibited Akt phosphorylation and reduced survivin expression resulting in increased apoptosis in FET/DNRII cells. We also show that exogenous TGF beta increased apoptosis in FET cells through repression of the PI3K/Akt/survivin pathway during GFDS. These results indicate that the PI3K/Akt/ survivin pathway is blocked by TGF beta signaling and that loss of autocrine TGF beta leads to increased cell survival during GFDS through the novel linkage of TGF beta-mediated repression of survivin expression. Inhibition of survivin function by dominant-negative approaches showed that this inhibitor of apoptosis family member is critical to cell survival in the FET/DNRII cells, thus indicating the importance of this target for TGF beta-mediated apoptosis.