Diacylglycerol Kinase Alpha is a Critical Signaling Node and Novel Therapeutic Target in Glioblastoma and Other Cancers
Dominguez, Charli, Neuroscience - Graduate School of Arts and Sciences, University of Virginia
Purow, Benjamin, Department of Neurology, University of Virginia
While Diacylglycerol kinase alpha (DGKα) has been linked to several signaling pathways related to cancer cell biology, it has been neglected as a target for cancer therapy. The attenuation of DGKα activity via DGKα-targeting siRNA and small-molecule inhibitors, R59022 and R59949, induced caspase-mediated apoptosis in glioblastoma cells and in other cancers, but lacked toxicity in non-cancerous cells. We determined that mTOR and HIF-1α are key targets of DGKα inhibition, in addition to its regulation of other oncogenes. DGKa regulates mTOR transcription via a unique pathway involving cyclic AMP. Lastly, we showed efficacy of DGKα inhibition with shRNA or a small-molecule agent in glioblastoma and melanoma xenograft treatment models, with growth delay and decreased vascularity. Subsequently, the inhibition of the DGKα product PA was investigated as a therapeutic target as well. Combination inhibition of the three PA synthetic pathways was significantly toxic to glioblastoma cells and other cancers, but lacked toxicity in non-cancerous cells. We showed that triple drug combination to inhibit the production of PA has a synergistic effect when compared to either single or double drug combinations. We believe that PA is a promising single target with high impact on cancer biology that can provide a novel approach for treatment-resistant cancers. Lastly, we identified and begun to investigate a compound, ritanserin, that is structurally similar to DGKα small-molecule inhibitors. We have preliminarily shown ritanserin to be toxic to GBM cells, safe in non-cancerous cells and to have an inhibitory affect on DGKα activity that is comparable to R59022 and R59949. This study establishes DGKα as a central signaling hub and a promising therapeutic target in the treatment of cancer, sets the foundation for PA as a potential single target, and begins to investigate ritanserin as a promising compound with potential for quick advancement to clinical trials for cancer therapy.
PHD (Doctor of Philosophy)
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