Activated Ras prevents downregulation of Bcl-X(L) triggered by detachment from the extracellular matrix. A mechanism of Ras-induced resistance to anoikis in intestinal epithelial cells.

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作者：

R Kirill，R Janusz，L Thomas，NM Dean，RS Kerbel，F Jorge

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摘要：

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 oncogenicrasleads to resistance to anoikis, and this resistance is required for the full manifestation of the malignant phenotype. Previously, we demonstrated thatras-induced inhibition of anoikis in intestinal epithelial cells results, in part, from theras-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 theras-transformed cells, the existence of at least another component of the apoptotic machinery mediating the effect of activatedrason 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-XL, and that activated H- or K-rasoncogenes completely abrogate this downregulation. In addition, we found that enforced downregulation of Bcl-XLin theras-transformed cells promotes anoikis and significantly inhibits tumorigenicity, indicating that disruption of the adhesion-dependent regulation of Bcl-XLis an essential part of the molecular changes associated with transformation byras. While theras-induced downregulation of Bak could be reversed by pharmacological inhibition of phosphatidylinositol 3 kinase (PI 3-kinase), the effect ofrason Bcl-XLwas PI 3-kinase– and mitogen-activated protein kinase (MAP kinase)–independent. We conclude thatras-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-XLexpression in the absence of the ECM.

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关键词：

apoptosis colorectal tumors cytoskeleton PI 3-kinase MAP kinase

DOI：

10.1083/jcb.149.2.447

被引量：

396

年份：

2000