Diacylglycerol kinase alpha is a critical signaling node and novel therapeutic target in glioblastoma and other cancers

Abstract

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. DGKα 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. This study establishes DGKα as a central signaling hub and a promising therapeutic target in the treatment of cancer.