TY - JOUR
T1 - TGF-β inhibits Akt-induced transformation in intestinal epithelial cells
AU - Cao, Yanna
AU - Deng, Chunyan
AU - Townsend, Courtney M.
AU - Ko, Tien C.
PY - 2006/8
Y1 - 2006/8
N2 - Background: During the early stages of colorectal carcinogenesis, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated, enabling the transformed cells to survive and grow in the absence of anchorage to extracellular matrix. Transforming growth factor β (TGF-β) is an important tumor suppressor in the colon, and it is inactivated during later stages of colorectal carcinogenesis. The purpose of this study was to determine whether TGF-β inhibits Akt-induced anchorage-independent growth and resistance to anoikis in gut epithelial cells. Methods: Rat intestinal epithelial cells (RIE-1) were infected with a retrovirus containing pLXSN-mAkt, and three independent clones were selected. Anchorage-independent growth was examined by colony formation in soft agar and cell counting in ultralow attachment plates. Anoikis was analyzed with the use of Annexin V staining. Results: All three clones of RIE-1/mAkt formed colonies in soft agar, which were decreased by TGF-β. TGF-β induced anoikis and treatment with a general caspase inhibitor, zVAD-fluoromethyl ketone, blocked TGF-β-mediated decrease in colony formation. Conclusions: TGF-β attenuated Akt-induced anchorage-independent growth in RIE-1 cells in part by enhancing anoikis. Our data demonstrate a novel tumor-suppressor activity of TGF-β and provide the molecular justification for the required activation of the PI3K/Akt pathway and the subsequent inactivation of TGF-β signaling during colorectal carcinogenesis.
AB - Background: During the early stages of colorectal carcinogenesis, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is activated, enabling the transformed cells to survive and grow in the absence of anchorage to extracellular matrix. Transforming growth factor β (TGF-β) is an important tumor suppressor in the colon, and it is inactivated during later stages of colorectal carcinogenesis. The purpose of this study was to determine whether TGF-β inhibits Akt-induced anchorage-independent growth and resistance to anoikis in gut epithelial cells. Methods: Rat intestinal epithelial cells (RIE-1) were infected with a retrovirus containing pLXSN-mAkt, and three independent clones were selected. Anchorage-independent growth was examined by colony formation in soft agar and cell counting in ultralow attachment plates. Anoikis was analyzed with the use of Annexin V staining. Results: All three clones of RIE-1/mAkt formed colonies in soft agar, which were decreased by TGF-β. TGF-β induced anoikis and treatment with a general caspase inhibitor, zVAD-fluoromethyl ketone, blocked TGF-β-mediated decrease in colony formation. Conclusions: TGF-β attenuated Akt-induced anchorage-independent growth in RIE-1 cells in part by enhancing anoikis. Our data demonstrate a novel tumor-suppressor activity of TGF-β and provide the molecular justification for the required activation of the PI3K/Akt pathway and the subsequent inactivation of TGF-β signaling during colorectal carcinogenesis.
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U2 - 10.1016/j.surg.2006.05.006
DO - 10.1016/j.surg.2006.05.006
M3 - Article
C2 - 16904986
AN - SCOPUS:33746855860
SN - 0039-6060
VL - 140
SP - 322
EP - 329
JO - Surgery
JF - Surgery
IS - 2
ER -