Diacylglycerol Kinase a Is a Critical Signaling Node and Novel Therapeutic Target in Glioblastoma and Other Cancers

Although diacylglycerol kinase alpha (DGK alpha) 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 DGK alpha activity via DGK alpha-targeting siRNA and small-molecule inhibitors R59022 and R59949 induced caspase-mediated apoptosis in glioblastoma cells and in other cancers, but lacked toxicity in noncancerous cells. We determined that mTOR and hypoxia-inducible factor-1 alpha (HIF-1 alpha) are key targets of DGK alpha inhibition, in addition to its regulation of other oncogenes. DGK alpha regulates mTOR transcription via a unique pathway involving cyclic AMP. Finally, we showed the efficacy of DGK alpha inhibition with short hairpin RNA or a small-molecule agent in glioblastoma and melanoma xenograft treatment models, with growth delay and decreased vascularity. This study establishes DGK alpha as a central signaling hub and a promising therapeutic target in the treatment of cancer. SIGNIFICANCE: DGK alpha, which converts diacylglycerol to phosphatidic acid, regulates critical oncogenic pathways, notably HIF-1 alpha and mTOR. DGK alpha knockdown and small-molecule inhibition are selectively toxic to human cancer cells but not normal human cells, and DGK alpha inhibition slows tumor growth, decreases angiogenesis, and increases mouse survival in xenograft models. (C) 2013 AACR.