title: Diacylglycerol kinase α is a critical signaling node and novel therapeutic target in glioblastoma and other cancers.
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.
authors.affiliation: Division of Neuro-Oncology, Department of Neurology, College of Nursing and Health Professions, University of Southern Indiana, Evansville, Indiana, USA.
authors.forename: Charli L
authors.initials: CL
authors.lastname: Dominguez
authors.forename: Desiree H
authors.initials: DH
authors.lastname: Floyd
authors.forename: Aizhen
authors.initials: A
authors.lastname: Xiao
authors.forename: Garrett R
authors.initials: GR
authors.lastname: Mullins
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Kefas
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xin
authors.forename: Melissa N
authors.initials: MN
authors.lastname: Yacur
authors.forename: Roger
authors.initials: R
authors.lastname: Abounader
authors.forename: Jae K
authors.initials: JK
authors.lastname: Lee
authors.forename: Gabriela Mustata
authors.initials: GM
authors.lastname: Wilson
authors.forename: Thurl E
authors.initials: TE
authors.lastname: Harris
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Purow
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019852:Diacylglycerol Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010880:Piperidines / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D052999:Quinazolinones / Q000008:administration & dosage; D034741:RNA, Small Interfering; D013844:Thiazoles / Q000008:administration & dosage
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010880:Piperidines; D011744:Pyrimidinones; D052999:Quinazolinones; D034741:RNA, Small Interfering; D013844:Thiazoles; C058544:R 59949; C047505:R 59022; D019852:Diacylglycerol Kinase
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