Transforming Growth Factor β Induces Apoptosis through Repressing the Phosphoinositide 3-Kinase/AKT/Survivin Pathway in Colon Cancer Cells

Abstract

FET cells, derived from an early-stage colon carcinoma, are nontumorigenic in athymic mice. Stable transfection of a dominant-negative transforming growth factor B (TGFB) type II receptor (DNRII) into FET cells that express autocrine TGFB shows loss of TGFB signaling and increased tumorigenicity in vivo indicating tumor suppressor activity of TGFB 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 TGFB in a ''fail-safe'' mechanism to generate cell death in response to this stress. Here, we document that loss of autocrine TGFB 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 TGFB 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 TGFB signaling and that loss of autocrine TGFB leads to increased cell survival during GFDS through the novel linkage of TGFB-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 TGFB-mediated apoptosis. [Cancer Res 2008;68(9):3152-60]

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

“…These results indicate that PDK4 regulates the expression of Bcl-2 and survivin. It has been shown that Bcl-2 and survivin protect colon cancer cells from stress-induced apoptosis (35,36) and that 5-FU induces apoptosis in colon cancer cell lines with modulation of Bcl-2 family proteins (37). To demonstrate the potential role of Bcl-2 and survivin in 5-FU-induced apoptosis in PDK4 knockdown cells, Bcl-2 and survivin were ectopically expressed individually in CBS/PDK4 sh-2 cells.…”

“…One important difference between 5-FU-sensitive and -resistant cells is TGF␤ signaling. Although 5-FU-sensitive RKO and HCT116 cells are defective in TGF␤ signaling because of the mutations in TGF␤ RII (3), 5-FU resistant FET and CBS cells are responsive or partially responsive to TGF␤ signaling, respectively (36,38). This suggests that the TGF␤ signaling pathway may play a role in the 5-FU response.…”

“…This suggests that the TGF␤ signaling pathway may play a role in the 5-FU response. To determine whether this is the case, a dominant negative RII (DNRII) construct was transfected into FET cells to inactivate TGF␤ signaling (6,36). Complementarily, wild-type RII cDNA was introduced into HCT116 cells to restore TGF␤ signaling (5).…”

Cytoplasmic localization of wild-type survivin is associated with constitutive activation of the PI3K/Akt signaling pathway and represents a favorable prognostic factor in patients with acute myeloid leukemia

“…Importantly, a body of evidence suggests that constitutive activation of mTORC1 in AML is independent of PI3K which in turn can be constitutively fully activated in an mTOR-independent manner. 29 Previous studies have demonstrated that PI3K/Akt inhibitors caused decreased expression of many proteins including survivin 17,18,[30][31][32] in solid tumors and hematologic malignancies. Additionally, it has been shown in a mouse model that internal tandem duplication of Flt3 regulates survivin expression via PI3K/Akt leading to aberrant progenitor cell proliferation and promoting leukemogenesis.…”

“…15 Additionally, it has been shown in a mouse model that internal tandem duplication of Flt-3 regulates survivin expression via PI3K/Akt leading to aberrant progenitor cell proliferation. 16 Although the importance of the PI3K/Akt/survivin pathway has been reported in lung and colon cancer, 17,18 its incidence and prognostic impact in AML have not been described.In this study we analyzed the subcellular compartment distribution of WT survivin and the splicing variants survivin-2B and survivin-Delta-Ex3 in AML patients, the correlation with PI3K/Akt pathway activation, and the possible impact on outcome. …”