Downregulation of the pro-apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells.
Anoikis is a form of programmed cell death induced in normal epithelial cells by detachment from the extracellular matrix [1] [2] [3]. In epithelial cells of the intestine and other organs, activated rasinduces resistance to anoikis [3] [4], but the actual molecular effectors directly involved in the apoptotic machinery that execute or block anoikis have not yet been identified. Bak, a pro-apoptotic member of the Bcl-2 family, is downregulated in a high proportion of colorectal tumours [5]. In addition, Bak is an important regulator of apoptosis in normal intestinal epithelial cells [6] [7]. Here, we show that activated rasinduces the downregulation of Bak in rat and human intestinal epithelial cells. This ras-induced downregulation of Bak expression could be suppressed by an inhibitor of phosphatidylinositol (PI) 3-kinase, an enzyme already implicated in ras-induced resistance to anoikis [8]. Ectopic expression of Bak in ras-transformed rat intestinal epithelial IEC-18 cells inhibited ras-induced resistance to anoikis and significantly reduced their tumorigenicity. We conclude, therefore, that the ability of rasto downregulate Bak, and the consequent resistance to anoikis, are essential components of the transforming capacity of this oncogene in intestinal epithelial cells.
Rosen
K
K
Department of Cancer Biology Research Sunnybrook Health Science Centre S-218 Research Building 2075 Bayview Avenue Toronto Ontario M4N 3M5 Canada.
Rak
J
J
Jin
J
J
Kerbel
R S
RS
Newman
M J
MJ
Filmus
J
J
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D002999:Clone Cells; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein
C494772:BAK1 protein, human; C494774:Bak1 protein, rat; D002867:Chromones; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050998:bcl-2 Homologous Antagonist-Killer Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one