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Cancer Discov. 2013 Jul;3(7):782-97. doi: 10.1158/2159-8290.CD-12-0215. Epub 2013 Apr 4.

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

Author information

1
Division of Neuro-Oncology, Department of Neurology, College of Nursing and Health Professions, University of Southern Indiana, Evansville, Indiana, USA.

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.

PMID:
23558954
PMCID:
PMC3710531
DOI:
10.1158/2159-8290.CD-12-0215
[Indexed for MEDLINE]
Free PMC Article

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