title: CK2 inhibition induced PDK4-AMPK axis regulates metabolic adaptation and survival responses in glioma.
abstract: Understanding mechanisms that link aberrant metabolic adaptation and pro-survival responses in glioma cells is crucial towards the development of new anti-glioma therapies. As we have previously reported that CK2 is associated with glioma cell survival, we evaluated its involvement in the regulation of glucose metabolism. Inhibition of CK2 increased the expression of metabolic regulators, PDK4 and AMPK along with the key cellular energy sensor CREB. This increase was concomitant with altered metabolic profile as characterized by decreased glucose uptake in a PDK4 and AMPK dependent manner. Increased PDK4 expression was CREB dependent, as exogenous inhibition of CREB functions abrogated CK2 inhibitor mediated increase in PDK4 expression. Interestingly, PDK4 regulated AMPK phosphorylation which in turn affected cell viability in CK2 inhibitor treated glioma cells. CK2 inhibitor 4,5,6,7-Tetrabromobenzotriazole (TBB) significantly retarded the growth of glioma xenografts in athymic nude mouse model. Coherent with the in vitro findings, elevated senescence, pAMPK and PDK4 levels were also observed in TBB-treated xenograft tissue. Taken together, CK2 inhibition in glioma cells drives the PDK4-AMPK axis to affect metabolic profile that has a strong bearing on their survival.
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India.
authors.forename: Deobrat
authors.initials: D
authors.lastname: Dixit
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India.
authors.forename: Fahim
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Ghildiyal
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India.
authors.forename: Shanker Datt
authors.initials: SD
authors.lastname: Joshi
authors.affiliation: National Brain Research Centre, Manesar, Haryana, India. Electronic address: ellora@nbrc.ac.in.
authors.forename: Ellora
authors.initials: E
authors.lastname: Sen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005910:Glioma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008819:Mice, Nude; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C405354:4,5,6,7-tetrabromobenzotriazole; D017362:Cyclic AMP Response Element-Binding Protein; C000631432:PDK4 protein, human; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D000255:Adenosine Triphosphate; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1; D005947:Glucose
keywords: AMPK; CK2; CREB; Glioblastoma; PDK4