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Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases

Oncogene volume 26, pages 4084–4094 (2007)Cite this article

Abstract

Secreted protein acidic and rich in cysteine (SPARC) is an extracellular glycoprotein expressed in several solid cancers, including malignant gliomas, upon adoption of metastatic or invasive behaviors. SPARC expression in glioma cells promotes invasion and survival under stress, the latter process dependent on SPARC activation of AKT. Here we demonstrate that downregulation of SPARC expression with short interfering RNA (siRNA) in glioma cells decreased tumor cell survival and invasion. SPARC siRNA reduced the activating phosphorylation of AKT and two cytoplasmic kinases, focal adhesion kinase (FAK) and integrin-linked kinase (ILK). We determined the contributions of FAK and ILK to SPARC effects using SPARC protein and cell lines engineered to overexpress SPARC. SPARC activated FAK and ILK in glioma cells previously characterized as responsive to SPARC. Downregulation of either FAK or ILK expression inhibited SPARC-mediated AKT phosphorylation, and targeting both FAK and ILK attenuated AKT activation more potently than targeting either FAK or ILK alone. Decreased SPARC-mediated AKT activation correlated with a reduction in SPARC-dependent invasion and survival upon the downregulation of FAK and/or ILK expression. These data further demonstrate the role of SPARC in glioma tumor progression through the activation of intracellular kinases that may provide novel therapeutic targets for advanced cancers.

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Acknowledgements

We thank Michael Cook for technical support. J Rich is a Damon Runyon-Lilly Clinical Investigator and Kimmel Scholar and supported by the Damon Runyon Cancer Research Foundation, the Sidney Kimmel Foundation for Cancer Research, the Pediatric Brain Tumor Foundation of the United States, the Childhood Brain Tumor Foundation and the USPHS Grants NS047409, NS054276, CA 108786 and CA 116659. A Hjelmeland is a Paul Brazen/American Brain Tumor Association Fellow, and she is also supported by the Southeastern Brain Tumor Foundation.

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Authors and Affiliations

  1. Department of Surgery, Duke University Medical Center, Durham, NC, USA

    Q Shi, S Bao, L Song, Q Wu, A B Hjelmeland & J N Rich

  2. Department of Pathology, Duke University Medical Center, Durham, NC, USA

    D D Bigner

  3. Department of Medicine, Duke University Medical Center, Durham, NC, USA

    J N Rich

  4. Department of Neurobiology, Duke University Medical Center, Durham, NC, USA

    J N Rich

  5. Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

    Q Shi, S Bao, L Song, Q Wu, D D Bigner, A B Hjelmeland & J N Rich

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Correspondence to J N Rich.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Shi, Q., Bao, S., Song, L. et al. Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases. Oncogene 26, 4084–4094 (2007). https://doi.org/10.1038/sj.onc.1210181

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