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Cyr61 Is Overexpressed in Gliomas and Involved in Integrin-Linked Kinase-Mediated Akt and ß-Catenin-TCF/Lef Signaling Pathways

¹ Division of Hematology/Oncology, ³ Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, and ⁴ Department of Pathology, UCLA School of Medicine, Los Angeles, California, and ² Institute for Nutritional Sciences, SIBS, Chinese Academy of Sciences, Shanghai, China

Cyr61 is a member of the CCN family of growth factors; these proteins are secreted and can act as ligands of distinct integrins. We show that Cyr61 can enhance tumorigenicity of glioma cells acting through activated integrin-linked kinase (ILK) to stimulate ß-catenin-TCF/Lef and Akt signaling pathways. Overexpression of Cyr61 occurred in highly tumorigenic glioma cell lines and in 68% of the most malignant glioblastoma multiforme brain tumors. Forced expression of Cyr61 in U343 glioma cells accelerated their growth in liquid culture, enhanced their anchorage-independent proliferation in soft agar, and significantly increased their ability to form large, vascularized tumors in nude mice. Overexpression of Cyr61 in the U343 cells led to the up-regulation of distinct integrins, including ß1 and ß3, which have been shown to interact with Cyr61 and ILK. The activity of ILK was increased dramatically in these cells. Overexpression of Cyr61 also resulted in the phosphorylation of glycogen synthase kinase-3ß and accumulation and nuclear translocation of ß-catenin, leading to activation of the ß-catenin-TCF/Lef-1 signaling pathway. Furthermore, forced expression of Cyr61 in the glioma cells activated phosphatidylinositol 3'-kinase pathway, resulting in prominent phosphorylation of Akt and the antiapoptotic protein Bad. Cyr61 appears to stimulate several signaling pathways in the development of gliomas.

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