TGF-beta inhibits Akt-induced transformation in intestinal epithelial cells.
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.
Cao
Yanna
Y
Department of Surgery, The University of Texas Medical Branch, Galveston, TX 77555-0737, USA.
Deng
Chunyan
C
Townsend
Courtney M
CM
Ko
Tien C
TC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D018929:Cell Culture Techniques; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D016212:Transforming Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt