Abstract 3083: A novel method of sonic hedgehog signaling activation in the chemoresistance of glioblastoma: A ligand-independent mechanism.

Abstract

Abstract Glioblastoma Multiforme (GMB) is the most common and lethal adult primary tumor of the central nervous system. Despite current chemotherapy with concomitant surgical resection and radiotherapy, GBM 5-year survival is ∼3%. A better understanding of the cellular pathways in tumor proliferation and survival is required for the development of new treatments. Previously, the Sonic Hedgehog pathway has been shown to be dysregulated in chemoresistant GBM. Pharmacological inhibition of SHH signaling with Cyclopamine enhanced GBM chemosensitivity to temozolomide (TMZ). SHH receptor, PTCH1, is tonically repressed by the ligandbut is activated by by receptor-mediated endocytosis of SHH. Here we show SHH signaling in GBM is ligand-independent and is initiated by post-transcriptional regulation of PTCH1. MicroRNA are small non-coding RNA molecules known to regulate a number of cell processes such as development and oncogenesis. As far as we are aware there is no report on microRNA in the regulation of PTCH1. Knockdown of Dicer, a Type III RNAase, which is required for microRNA synthesis, increased the cellular toxicity to TMZ, thus revealing the importance of microRNA in GBM chemoresistance. We have indentified and characterized PTCH as a functional target of microRNA-9 (miR-9) in both non-neural cell lines as well as GBM cell lines. Overexpression of miR-9 in GBM cells results in downstream pathway activation and resistance to TMZ treatment. We also explored a number of mir-9/PTCH1-dependent mechanisms of chemoresistance and uncovered downstream upregulation of ATP-binding cassette drug efflux transporters, MDR1 and ABCG2. Taken together, our data indicate a role for miRNA9 in the acquisition of chemoresistance in GBMs and may serve as novel therapeutic targets. Citation Format: Jessian L. Munoz, Pranela Rameshwar. A novel method of sonic hedgehog signaling activation in the chemoresistance of glioblastoma: A ligand-independent mechanism. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3083. doi:10.1158/1538-7445.AM2013-3083