Increased Bcl-xL expression mediates v-Src-induced resistance to anoikis in intestinal epithelial cells.
Acquisition of resistance to anoikis (detachment-induced apoptosis) is considered to be a requirement for transformed intestinal epithelial cells to invade surrounding tissues and metastasize to distant organs. Increased Src kinase activity, which is a feature of a large proportion of colorectal cancers, has been identified as one of the factors that can contribute to anoikis resistance. However, the molecular mechanism by which high levels of Src activity contribute to anoikis resistance in intestinal epithelial cells is unknown. Here we show that high Src activity confers resistance to anoikis in intestinal epithelial cells, at least in part, by inducing Bcl-xL overexpression, and that this induction is mediated by the MEK/MAPK pathway. Based on the findings reported here, and on our previous study showing that Bcl-xL plays a critical role in ras-induced resistance to anoikis, we propose that the increased Bcl-xL levels found in colorectal cancers play a significant role in the induction of resistance to anoikis during the progression of this disease.
Coll
Mariano Loza
ML
Sunnybrook and Women's College Health Science Center, Division of Molecular and Cell Biology, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
Rosen
Kirill
K
Ladeda
Virginia
V
Filmus
Jorge
J
D000818:Animals; D023102:Anoikis; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology; D005786:Gene Expression Regulation; D007413:Intestinal Mucosa / Q000166:cytology; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D051381:Rats; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D015688:Oncogene Protein pp60(v-src); D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases