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J. Biol. Chem., Vol. 280, Issue 45, 37383-37392, November 11, 2005

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ras Oncogene Triggers Up-regulation of cIAP2 and XIAP in Intestinal Epithelial Cells

EPIDERMAL GROWTH FACTOR RECEPTOR-DEPENDENT AND -INDEPENDENT MECHANISMS OF ras-INDUCED TRANSFORMATION^*

Zaiping Liu, Hongbing Li1, Mathieu Derouet1, Jorge Filmus, Eric C. LaCasse¶, Robert G. Korneluk||, Robert S. Kerbel, and Kirill V. Rosen2

From the Departments of Pediatrics and Biochemistry and Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada, Department of Molecular and Cellular Biology, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada, ^¶Aegera Oncology Inc., Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario K1H 8L1, Canada, and ^||Children's Hospital of Eastern Ontario Research Institute and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada

Detachment of normal epithelial cells from the extracellular matrix (ECM) triggers apoptosis, a phenomenon called anoikis. Conversely, carcinomas (cancers of epithelial origin) represent three-dimensional disorganized multicellular masses in which cells are deprived of adhesion to the ECM but remain viable. Resistance of cancer cells to anoikis is thought to be critical for tumor progression. However, the knowledge about molecular mechanisms of this type of resistance remains limited. Herein we report that ras oncogene, an established inhibitor of anoikis, triggers a significant upregulation of anti-apoptotic proteins cIAP2 and XIAP in intestinal epithelial cells. We also observed that the effect of ras on cIAP2 requires ras-induced autocrine production of transforming growth factor (TGF-), a ligand for epidermal growth factor receptor, whereas ras-triggered up-regulation of XIAP is TGF--independent. Moreover, overexpression of either cIAP2 or XIAP in nonmalignant intestinal epithelial cell was found to block anoikis. In addition, an established IAP antagonist Smac or Smac-derived cell-permeable peptide suppressed ras-induced anoikis resistance and subsequent anchorage-independent growth of ras-transformed cells. We conclude that ras-induced overexpression of cIAP2 and XIAP significantly contributes to the ability of ras-transformed intestinal epithelial cells to survive in the absence of adhesion to the ECM and grow in a three-dimensional manner.

Received for publication, April 5, 2005 , and in revised form, July 25, 2005.

^* This work was supported by Canadian Institutes of Health Research Operating Grant IC1–71813. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipients of Postdoctoral Traineeship awards from the Dalhousie Cancer Research Training Program.

² To whom correspondence should be addressed: Atlantic Research Centre, Rm. C-302, CRC, 5849 University Ave., Halifax, Nova Scotia B3H 4H7, Canada. Tel.: 902-494-7088; Fax: 902-494-1394; E-mail: Kirill.Rosen{at}Dal.Ca.

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