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J. Biol. Chem., Vol. 281, Issue 21, 14738-14747, May 26, 2006

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Oncogenic Ras Inhibits Anoikis of Intestinal Epithelial Cells by Preventing the Release of a Mitochondrial Pro-apoptotic Protein Omi/HtrA2 into the Cytoplasm^*

Zaiping Liu¹, Hongbing Li¹², Mathieu Derouet¹², Alexander Berezkin¹, Takehiko Sasazuki, Senji Shirasawa, and Kirill Rosen³

From the Departments of Pediatrics & Biochemistry and Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada and the Department of Pathology, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjyuku-ku, Tokyo 162-8655, Japan

Resistance of cancer cells to anoikis, apoptosis induced by cell detachment from the extracellular matrix, is thought to represent a critical feature of the malignant phenotype. Mechanisms that control anoikis of normal and cancer cells are understood only in part. Previously we found that anoikis of non-malignant intestinal epithelial cells is driven by detachment-induced down-regulation of Bcl-X_L, a protein that blocks apoptosis through preventing the release of death-promoting factors from the mitochondria. Mitochondrial proteins the release of which causes anoikis are presently unknown. Similar to what was previously observed by others for keratinocytes and fibroblasts, we show here that anoikis of intestinal epithelial cells does not involve caspase-9, a target of a mitochondrial protein cytochrome c. Furthermore, Smac/Diablo, another mitochondrial pro-apoptotic factor, does not appear to play a role in detachment-dependent apoptosis of these cells either. Instead, anoikis of intestinal epithelial cells is triggered by the release of a mitochondrial protein Omi/HtrA2, an event driven by detachment-induced down-regulation of Bcl-X_L. Moreover, we established that oncogenic ras inhibits anoikis by preventing the release of Omi/HtrA2. This effect of ras required ras-induced down-regulation of a pro-apoptotic protein Bak and could be blocked by an inhibitor of phosphoinositide 3-kinase, a target of Ras that was previously implicated by us in the down-regulation of Bak and blockade of anoikis. We conclude that Omi/HtrA2 is an inducer of anoikis and an important regulator of ras-induced transformation.

Received for publication, August 5, 2005 , and in revised form, January 9, 2006.

^* This work was supported by the Terry Fox Foundation under National Cancer Institute of Canada Grant 015397. 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 These authors contributed equally to this work.

² Recipients of Postdoctoral Traineeship Awards from the Dalhousie Cancer Research Training Program.

³ To whom correspondence should be addressed: 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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