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

ABSTRACT: Although diacylglycerol kinase ? (DGK?) 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? activity via DGK?-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? (HIF-1?) are key targets of DGK? inhibition, in addition to its regulation of other oncogenes. DGK? regulates mTOR transcription via a unique pathway involving cyclic AMP. Finally, we showed the efficacy of DGK? 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? as a central signaling hub and a promising therapeutic target in the treatment of cancer.

SUBMITTER: Dominguez CL 

PROVIDER: S-EPMC3710531 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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

Dominguez Charli L CL   Floyd Desiree H DH   Xiao Aizhen A   Mullins Garrett R GR   Kefas Benjamin A BA   Xin Wenjun W   Yacur Melissa N MN   Abounader Roger R   Lee Jae K JK   Wilson Gabriela Mustata GM   Harris Thurl E TE   Purow Benjamin W BW  

Cancer discovery 20130404 7

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,  ...[more]

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