Journal
CANCER RESEARCH
Volume 68, Issue 9, Pages 3152-3160Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-5348
Keywords
-
Categories
Funding
- NCI NIH HHS [P50 CA 36727, R37 CA 38173, R01 CA 72001] Funding Source: Medline
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available