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© The Rockefeller University Press, 0021-9525/2000//447 $5.00
The Journal of Cell Biology, Volume 149, Number 2, , 2000 447-456

Activated ras Prevents Downregulation of Bcl-X_L Triggered by Detachment from the Extracellular Matrix

Kirill Rosen^a,b, Janusz Rak^a,b, Thomas Leung^a,b, Nicholas M. Dean^c, Robert S. Kerbel^a,b, and Jorge Filmus^a,b

^a Division of Cancer Biology Research, Sunnybrook and Women's College Health Science Centre,
^b Department of Medical Biophysics, University of Toronto, Ontario, Canada M4N 3M5
^c Isis Pharmaceuticals, Carlsbad, California 92008
Division of Cancer Biology Research, Sunnybrook Health Science Centre, S-218, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5.(416) 480-6100, ext

Detachment of epithelial cells from the extracellular matrix (ECM) results in a form of apoptosis often referred to as anoikis. Transformation of intestinal epithelial cells by oncogenic ras leads to resistance to anoikis, and this resistance is required for the full manifestation of the malignant phenotype. Previously, we demonstrated that ras-induced inhibition of anoikis in intestinal epithelial cells results, in part, from the ras-induced constitutive downregulation of Bak, a pro-apoptotic member of the Bcl-2 family. Since exogenous Bak could only partially restore susceptibility to anoikis in the ras-transformed cells, the existence of at least another component of the apoptotic machinery mediating the effect of activated ras on anoikis was suggested. Indeed, here we show that, in nonmalignant rat and human intestinal epithelial cells, detachment from the ECM or disruption of the cytoskeleton results in a significant downregulation of the antiapoptotic effector Bcl-X_L, and that activated H- or K-ras oncogenes completely abrogate this downregulation. In addition, we found that enforced downregulation of Bcl-X_L in the ras-transformed cells promotes anoikis and significantly inhibits tumorigenicity, indicating that disruption of the adhesion-dependent regulation of Bcl-X_L is an essential part of the molecular changes associated with transformation by ras. While the ras-induced downregulation of Bak could be reversed by pharmacological inhibition of phosphatidylinositol 3 kinase (PI 3-kinase), the effect of ras on Bcl-X_L was PI 3-kinase– and mitogen-activated protein kinase (MAP kinase)–independent. We conclude that ras-induced resistance to anoikis in intestinal epithelial cells is mediated by at least two distinct mechanisms: one that triggers downregulation of Bak and another that stabilizes Bcl-X_L expression in the absence of the ECM.

Key Words: apoptosis • colorectal tumors • cytoskeleton • PI 3-kinase • MAP kinase

© 2000 The Rockefeller University Press

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