Abstract
Although diacylglycerol kinase α (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 noncancerous cells. We determined that mTOR and hypoxia-inducible factor-1α (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. Finally, we showed the efficacy of DGKα 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 DGKα as a central signaling hub and a promising therapeutic target in the treatment of cancer.
SIGNIFICANCE: DGKα, which converts diacylglycerol to phosphatidic acid, regulates critical oncogenic pathways, notably HIF-1α and mTOR. DGKα knockdown and small-molecule inhibition are selectively toxic to human cancer cells but not normal human cells, and DGKα inhibition slows tumor growth, decreases angiogenesis, and increases mouse survival in xenograft models. Cancer Discov; 3(7); 1–16. ©2013 AACR.
Footnotes
Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).
- Received May 11, 2012.
- Revision received March 29, 2013.
- Accepted April 1, 2013.
- ©2013 American Association for Cancer Research.