Abstract
Glioblastoma, the most common primary malignant brain tumor, is incurable with current therapies. Genetic and molecular analyses demonstrate that glioblastomas frequently display mutations that activate receptor tyrosine kinase (RTK) and Pi-3 kinase (PI3K) signaling pathways. In Drosophila melanogaster, activation of RTK and PI3K pathways in glial progenitor cells creates malignant neoplastic glial tumors that display many features of human glioblastoma. In both human and Drosophila, activation of the RTK and PI3K pathways stimulates Akt signaling along with other as-yet-unknown changes that drive oncogenesis. We used this Drosophila glioblastoma model to perform a kinome-wide genetic screen for new genes required for RTK- and PI3K-dependent neoplastic transformation. Human orthologs of novel kinases uncovered by these screens were functionally assessed in mammalian glioblastoma models and human tumors. Our results revealed that the atypical kinases RIOK1 and RIOK2 are overexpressed in glioblastoma cells in an Akt-dependent manner. Moreover, we found that overexpressed RIOK2 formed a complex with RIOK1, mTor, and mTor-complex-2 components, and that overexpressed RIOK2 upregulated Akt signaling and promoted tumorigenesis in murine astrocytes. Conversely, reduced expression of RIOK1 or RIOK2 disrupted Akt signaling and caused cell cycle exit, apoptosis, and chemosensitivity in glioblastoma cells by inducing p53 activity through the RpL11-dependent ribosomal stress checkpoint. These results imply that, in glioblastoma cells, constitutive Akt signaling drives RIO kinase overexpression, which creates a feedforward loop that promotes and maintains oncogenic Akt activity through stimulation of mTor signaling. Further study of the RIO kinases as well as other kinases identified in our Drosophila screen may reveal new insights into defects underlying glioblastoma and related cancers and may reveal new therapeutic opportunities for these cancers.
Highlights
Glioblastoma (GBM), the most common primary malignant brain tumor, infiltrates the brain, grows rapidly, and is refractory to current therapies
To date, no specific function has been ascribed to RIOK1 or RIOK2 in the context of EGFR or Pi-3 kinase (PI3K) signaling. In this manuscript we demonstrate that RIOK1 and RIOK2 become overexpressed in GBM tumor cells relative to normal brain cells; that RIOK1 and RIOK2 overexpression occurs in response to constitutive Akt signaling; that RIOK2 forms a complex with RIOK1, mTor, and other signaling components to drive activation of Akt signaling and tumorigenesis; and that, in GBM cells, RIOK1 or RIOK2 loss causes a reduction in Akt signaling and provokes p53-dependent apoptosis, cell cycle exit, and chemosensitivity through the RpL11-dependent ribosomal stress checkpoint
From a Drosophila genetic screen, we identified genes encoding 16 novel kinases that affect EGFR- and PI3K- dependent neoplastic glial transformation
Summary
Glioblastoma (GBM), the most common primary malignant brain tumor, infiltrates the brain, grows rapidly, and is refractory to current therapies. DEGFR and other constitutively active mutant forms of EGFR found in GBMs potently drive tumor cell survival, migration, and proliferation [2,3]. The most frequent mutation in the PI3K pathway in GBM is loss of the PTEN lipid phosphatase, which results in unopposed signaling through PI3K and robust stimulation of Akt, especially in the context of EGFR activation [1]. While several normal effectors of RTK and PI3K signaling, such as Ras, Akt, and mTor, are used by EGFR and PI3K in GBM and are required for gliomagenesis [1], constitutive activation of RTK and PI3K pathways may evoke changes distinct from those induced by Author Summary
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