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J. Biol. Chem., Vol. 279, Issue 44, 46113-46121, October 29, 2004

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Expression of Kinase-defective Mutants of c-Src in Human Metastatic Colon Cancer Cells Decreases Bcl-x_L and Increases Oxaliplatin- and Fas-induced Apoptosis^*

Gareth J. Griffiths, Mei Yee Koh, Valerie G. Brunton¶, Christopher Cawthorne, Natalie A. Reeves, Martin Greaves, Michael J. Tilby||, D. Graham Pearson**, Christopher J. Ottley**, Paul Workman, Margaret C. Frame¶, and Caroline Dive¶¶

From the Cancer Research UK Paterson Institute for Cancer Research, Manchester, and School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M20 4BX, ^¶Cancer Research UK Beatson Institute, Glasgow GG1 1BD, ^||Northern Institute for Cancer Research, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, ^**Department of Geological Sciences, Durham University, Durham DH1 3HP, and Cancer Research UK Centre for Cancer Therapeutics at The Institute of Cancer Research, Sutton SM2 5NG, United Kingdom

Tumor resistance to current drugs prevents curative treatment of human colon cancer. A pressing need for effective, tumor-specific chemotherapies exists. The non-receptor-tyrosine kinase c-Src is overexpressed in >70% of human colon cancers and represents a tractable drug target. KM12L4A human metastatic colon cancer cells were stably transfected with two distinct kinase-defective mutants of c-src. Their response to oxaliplatin, to SN38, the active metabolite of irinotecan (drugs active in colon cancer), and to activation of the death receptor Fas was compared with vector control cells in terms of cell cycle arrest and apoptosis. Both kinase-defective forms of c-Src co-sensitized cells to apoptosis induced by oxaliplatin and Fas activation but not by SN38. Cells harboring kinase-defective forms of c-Src carrying function blocking point mutations in SH3 or SH2 domains were similarly sensitive to oxaliplatin, suggesting that reduction in kinase activity and not a Src SH2-SH3 scaffold function was responsible for the observed altered sensitivity. Oxaliplatin-induced apoptosis, potentiated by kinase-defective c-Src mutants, was dependent on activation of caspase 8 and associated with Bid cleavage. Each of the stable cell lines in which kinase-defective mutants of c-Src were expressed had reduced levels of Bcl-x_L. However, inhibition of c-Src kinase activity by PP2 in vector control cells did not alter the oxaliplatin response over 72 h nor did it reduce Bcl-x_L levels. The data suggest that longer term suppression of Src kinase activity may be required to lower Bcl-x_L levels and sensitize colon cancer cells to oxaliplatin-induced apoptosis.

Received for publication, July 28, 2004 , and in revised form, August 23, 2004.

^* The work was funded by Cancer Research UK via Programme Grants (to C. D., M. C. F., and P. W.). 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.

These authors contributed equally.

A Cancer Research UK Life Fellow.

^¶¶ To whom correspondence should be addressed: Cellular and Molecular Pharmacology Group, Paterson Institute for Cancer Research, Wilmslow Rd., Manchester, M20 4BX, UK. Tel.: 44-161-446-3036; Fax: 44-161-446-3109; E-mail: cdive{at}picr.man.ac.uk.

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