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J. Biol. Chem., Vol. 279, Issue 50, 52200-52209, December 10, 2004

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Secreted Protein Acidic, Rich in Cysteine (SPARC), Mediates Cellular Survival of Gliomas through AKT Activation^*

Qing Shi, Shideng Bao, Jill A. Maxwell, Elizabeth D. Reese, Henry S. Friedman¶, Darell D. Bigner||, Xiao-Fan Wang, and Jeremy N. Rich**

From the Department of Surgery, the Department of Pharmacology and Cancer Biology, the ^¶Department of Pediatrics, the ^||Department of Pathology, ^**Division of Neurology, and the Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710

Secreted protein acidic, rich in cysteine (SPARC), is an extracellular matrix protein expressed in many advanced cancers, including malignant gliomas. We and others have previously shown that human glioma cell lines engineered to overexpress SPARC adopt an invasive phenotype. We now show that SPARC expression increases cell survival under stress initiated by serum withdrawal through a decrease in apoptosis. Phosphatidylinositol 3-OH kinase/AKT is a potent pro-survival pathway that contributes to the malignancy of gliomas. Cells expressing SPARC display increased AKT activation with decreased caspase 3/7 activity. Exogenous SPARC rapidly induces AKT phosphorylation, an effect that is blocked by a neutralizing SPARC antibody. Furthermore, AKT activation is essential for the anti-apoptotic effects of SPARC as the decreased apoptosis and caspase activity associated with SPARC expression can be blocked with dominant-negative AKT or a specific AKT inhibitor. As tumor cells face stressful microenvironments particularly during the process of invasion, these results suggest that SPARC functions, in part, to promote tumor progression by enabling tumor cells to survive under stressful conditions.

Received for publication, August 23, 2004 , and in revised form, September 27, 2004.

^* This work was supported in part by funds from the Pediatric Brain Tumor Foundation of the United States (to J. N. R.), Accelerate Brain Cancer Cure (to J. N. R.), Southeastern Brain Tumor Foundation (to J. N. R.), and by National Institutes of Health Grant NS047409 (to J. N. R.). 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.

A Damon Runyon-Lilly Clinical Investigator and a Sidney Kimmel Cancer Foundation Scholar. To whom correspondence should be addressed: Division of Neurology, Duke University Medical Center, Box 2900, Durham, NC 27710. Tel.: 919-681-1693; Fax: 919-684-6514; E-mail: rich0001{at}mc.duke.edu.

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