Abstract
Glioblastoma multiforme (GBM) is the most aggressive and prevalent form of primary brain cancer and is incurable. Amplification, mutation, and/or overexpression of the EGFR receptor tyrosine kinase and activating mutations in components of the PI3K pathway are common in GBM tumors, although the pathways that act downstream of EGFR and PI3K to drive tumorigenesis remain poorly understood. To better understand the underlying biology of tumorigenesis, we use a Drosophila melanogaster GBM model in which malignant neoplastic tumors arise from glial progenitor cells overexpressing activated oncogenic versions of EGFR and PI3K and identified Right-Open-Reading-Frame-2 (RIOK2), an atypical serine-threonine kinase, as a possible driver of EGFR-PI3K-dependent GBM. To elucidate downstream targets of RIOK2, we conducted preliminary immunoprecipitation experiments of RIOK2 from patient-derived GBM cell cultures coupled with proteomics and identified several novel RNA-binding proteins (RBPs) as binding partners and potential substrates of RIOK2. Subsequent experiments using our Drosophila GBM model show that RBP knock-down drastically reduced aberrant glial cell proliferation and invasion, similar to RIOK2 knock-down. Furthermore, co-immunoprecipitation experiments using patient derived primary GBM cells reveal that RIOK2 and novel RBPs are co-IPed and may operate in a complex. Moreover, RNA-binding protein immunoprecipitations (RIP) suggest that RIOK2 is associated with a number of oncogenic mRNAs. Based on our preliminary results, we hypothesize that RIOK2 drives tumorigenesis by modulating the activity of RBPs, and that this promotes the translation of RBP target mRNAs to drive tumor cell proliferation and survival.