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 beta (TGF-beta) 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-beta 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-beta. TGF-beta induced anoikis and treatment with a general caspase inhibitor, zVAD-fluoromethyl ketone, blocked TGF-beta-mediated decrease in colony formation. CONCLUSIONS: TGF-beta 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-beta and provide the molecular justification for the required activation of the PI3K/Akt pathway and the subsequent inactivation of TGF-beta signaling during colorectal carcinogenesis.
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 beta (TGF-beta) 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-beta 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-beta. TGF-beta induced anoikis and treatment with a general caspase inhibitor, zVAD-fluoromethyl ketone, blocked TGF-beta-mediated decrease in colony formation. CONCLUSIONS:TGF-beta 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-beta and provide the molecular justification for the required activation of the PI3K/Akt pathway and the subsequent inactivation of TGF-beta signaling during colorectal carcinogenesis.
Authors: Xianghua Liu; Junmei Zhao; Fazhi Li; Yan-shi Guo; Mark R Hellmich; Courtney M Townsend; Yanna Cao; Tien C Ko Journal: Regul Pept Date: 2009-07-23
Authors: Porfirio Nava; Christopher T Capaldo; Stefan Koch; Keli Kolegraff; Carl Robert Rankin; Attila E Farkas; Mattie E Feasel; Linheng Li; Caroline Addis; Charles A Parkos; Asma Nusrat Journal: EMBO Rep Date: 2011-03-04 Impact factor: 8.807
Authors: Yanna Cao; Xuxia Gao; Weili Zhang; Guohua Zhang; Anthony K Nguyen; Xianghua Liu; Fernando Jimenez; Charles S Cox; Courtney M Townsend; Tien C Ko Journal: Am J Physiol Gastrointest Liver Physiol Date: 2011-03-31 Impact factor: 4.052
Authors: Yanna Cao; Weili Zhang; Xuxia Gao; Guohua Zhang; Miriam Falzon; Courtney M Townsend; Mark R Hellmich; Tien C Ko Journal: Regul Pept Date: 2013-03-13
Authors: Y Cao; X Liu; W Zhang; X Deng; H Zhang; Y Liu; L Chen; E A Thompson; C M Townsend; T C Ko Journal: Oncogene Date: 2009-01-12 Impact factor: 9.867