Abstract
1683
Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix glycoprotein overexpressed in malignant gliomas and other solid cancers. In a gene expression study, we recently demonstrated that increased SPARC expression is associated with poor prognosis in older glioblastoma patients. Forced expression of SPARC increases glioma invasion associated with increased matrix metalloproteinase expression. Also, SPARC activates the pro-survival AKT pathway to increase glioma tumor cell survival upon serum withdrawal. To determine potential SPARC signal transducers upstream of AKT, we examined the activation state of kinases that are activated in gliomas and mediate invasion. While several transmembrane growth factor receptor tyrosine kinases are not activated by SPARC, we now demonstrate that SPARC acutely activates both focal adhesion kinase (FAK) and integrin-linked kinase (ILK). SiRNA suppression of either FAK or ILK expression reduces SPARC activation of AKT with a near complete inhibition by combined targeting of FAK and ILK expression. SPARC-mediated activation of FAK and ILK contribute to the biological effects of SPARC as suppression of FAK or ILK expression attenuates the effects of SPARC on both glioma invasion and cellular survival. SPARC induces a novel interaction of ILK and FAK as both exogenous SPARC and genetic expression of SPARC induces a complex of ILK and FAK. SPARC has been linked to tumor progression in several advanced cancers. The identification of a signal transduction pathway mediating the effects of SPARC may provide a marker of tumor dependence on specific signal transduction elements.
- American Association for Cancer Research