Abstract 1410: TIP-1 regulates Glioma invasion through small GTPases

Abstract Therapy resistance and invasion are two common features of malignant glioma. Our previous studies showed that TIP-1 regulates sensitivity of glioma cells to ionizing radiation. It was also found that TIP-1 protein level was elevated in human malignant glioma compared to the normal brain tissue counterparts, and correlated with the malignancy of gliomas. This observation was supported with a survival study within animal models, in which TIP-1 knockdown within glioma cell lines significantly retarded progression of the intracranially implanted tumors and extended survival time of the mice. In vitro and in vivo studies indicated that it is the reduced migration and invasion capability, but not the cell proliferation rate, that contributed to the retarded tumor progression of gliomas with TIP-1 knockdown. The glioma cells with TIP-1 knockdown also showed morphological changes with reorganized cytoskeleton and reduced efficiency of reorientation in directional migration. TIP-1 was reported to associate to beta-catenin and Rhotekin, two proteins that are involved in the cell skeleton reorganization and cell migration. Their interactions are through the single PDZ domain within TIP-1 and the classic Type I PDZ-binding motifs located at the carboxyl terminus of beta-catenin and Rhotekin respectively. It was found that TIP-1 knockdown altered intracellular location of Rhotekin. Mislocalization of Rhotekin at the cell migration leading edge resulted in irregular activation of RhoA, which generally regulates cell rear body retraction. Further, we identified that beta-PIX shares a similar PDZ-binding motif and associates to TIP-1 in vitro and in vivo. Beta-PIX is recruited to the leading edge by Scribble for Rac1 or Cdc42 activation and thus regulates cell front protrusion. Knockdown of TIP-1 within the invasive glioma cells disrupted the association of beta-PIX and Scribble, resulted in mislocalization of beta-PIX and reduced Rac1 activation. Taken together, these data illustrated that TIP-1 is one critical modulator in migration of the invasive glioma through regulating two small GTPases (RhoA and Rac1), and targeting TIP-1 might represent one novel approach to treat the highly invasive and mortal glioma tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1410. doi:10.1158/1538-7445.AM2011-1410