title: Gambogic acid induces EGFR degradation and Akt/mTORC1 inhibition through AMPK dependent-LRIG1 upregulation in cultured U87 glioma cells.
abstract: Glioblastoma multiforme (GBM) is the most common malignant tumor in adults' central nervous system (CNS). The development of novel anti-cancer agents for GBM is urgent. In the current study, we found that gambogic acid induced growth inhibition and apoptosis in cultured U87 glioma cells, which was associated with Akt/mTORC1 (mTOR complex 1) signaling in-activation. To restore Akt activation by introducing a constitutively active (CA) Akt attenuated gambogic acid-induced cytotoxicity against U87 cells. For mechanism study, we found that gambogic acid induced LRIG1 (leucine-rich repeat and Ig-like domain-containing-1) upregulation, which was responsible for EGFR (epidermal growth factor receptor) degradation and its downstream Akt/mTORC1 inhibition. Further, we provided evidence to support that AMPK (AMP-activated protein kinase) activation mediated gambogic acid-induced LRIG1 upregulation, U87 cell apoptosis and growth inhibition, while AMPK inhibition by shRNA or compound C reduced gambogic acid-induced EGFR/Akt inhibition and cytotoxicity in U87 cells. We here proposed novel signaling mechanism mediating gambogic acid-induced cytotoxic effects in glioma cells.
authors.affiliation: Department of Neurosurgery, Ruijin Hospital affiliated to Shanghai Jiao-tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Xin-yao
authors.initials: XY
authors.lastname: He
authors.forename: Xian-jin
authors.initials: XJ
authors.lastname: Liu
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Liu-guan
authors.initials: LG
authors.lastname: Bian
authors.forename: Wei-guo
authors.initials: WG
authors.lastname: Zhao
authors.forename: Jian-kang
authors.initials: JK
authors.lastname: Shen
authors.forename: Qing-fang
authors.initials: QF
authors.lastname: Sun
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D046912:Multiprotein Complexes; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation / Q000187:drug effects; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; D044004:Xanthones; C052659:gambogic acid; D066246:ErbB Receptors; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases