title: GSK621 Targets Glioma Cells via Activating AMP-Activated Protein Kinase Signalings.
abstract: Here, we studied the anti-glioma cell activity by a novel AMP-activated protein kinase (AMPK) activator GSK621. We showed that GSK621 was cytotoxic to human glioma cells (U87MG and U251MG lines), possibly via provoking caspase-dependent apoptotic cell death. Its cytotoxicity was alleviated by caspase inhibitors. GSK621 activated AMPK to inhibit mammalian target of rapamycin (mTOR) and downregulate Tetraspanin 8 (Tspan8) in glioma cells. AMPK inhibition, through shRNA knockdown of AMPKα or introduction of a dominant negative (T172A) AMPKα, almost reversed GSK621-induced AMPK activation, mTOR inhibition and Tspan8 degradation. Consequently, GSK621's cytotoxicity in glioma cells was also significantly attenuated by AMPKα knockdown or mutation. Further studies showed that GSK621, at a relatively low concentration, significantly potentiated temozolomide (TMZ)'s sensitivity and lethality against glioma cells. We summarized that GSK621 inhibits human glioma cells possibly via activating AMPK signaling. This novel AMPK activator could be a novel and promising anti-glioma cell agent.
authors.affiliation: Department of Neurosurgery, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Stereotactic and Functional Neurosurgery, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Stereotactic and Functional Neurosurgery, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, P.R. China.
authors.forename: Shi-Kun
authors.initials: SK
authors.lastname: Zhan
authors.affiliation: Department of Stereotactic and Functional Neurosurgery, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, P.R. China.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Pan
authors.affiliation: Department of Neurosurgery, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, P.R. China.
authors.forename: Liu-Guan
authors.initials: LG
authors.lastname: Bian
authors.affiliation: Department of Stereotactic and Functional Neurosurgery, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, P.R. China.
authors.forename: Bomin
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, P.R. China.
authors.forename: Qing-Fang
authors.initials: QF
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200025, P.R. China.
authors.forename: Si-Jian
authors.initials: SJ
authors.lastname: Pan
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077204:Temozolomide; D059470:Tetraspanins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C000606536:GSK621; D007093:Imidazoles; D011744:Pyrimidinones; C065609:TSPAN8 protein, human; D059470:Tetraspanins; D003606:Dacarbazine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000077204:Temozolomide