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 cel ls by detachment from the extracellular matrix [1-3]. In epithelial cells o f the intestine and other organs, activated ras induces resistance to anoik is [3,4], but the actual molecular effecters directly involved in the apopt otic 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 reg ulator of apoptosis in normal intestinal epithelial cells [6,7]. Here, we s how that activated ras induces the downregulation of Bak in rat and human i ntestinal epithelial cells, This ras-induced downregulation of Bak expressi on could be suppressed by an inhibitor of phosphatidylinositol (PI) 3 kinas e, an enzyme already implicated in ras induced resistance to anoikis [8]. E ctopic expression of Bak in res-transformed rat intestinal epithelial IEC-1 8 cells inhibited ras-induced resistance to anoikis and significantly reduc ed their tumorigenicity, We conclude, therefore, that the ability of res to downregulate Bak, and the consequent resistance to anoikis, are essential components of the transforming capacity of this oncogene in intestinal epit helial cells. (C) Current Biology Ltd ISSN 0960-9822.