Gambogic acid induces EGFR degradation and Akt/mTORC1 inhibition through AMPK dependent-LRIG1 upregulation in cultured U87 glioma cells

•Gambogic acid induces growth inhibition and apoptosis in cultured U87 glioma cells.•Gambogic acid inhibits Akt/mTORC1 signaling in cultured U87 glioma cells.•LRIG1 induction by gambogic acid promotes EGFR degradation.•AMPK activation mediates gambogic acid-induced LRIG1 upregulation and cytotoxicit...

Full description

Saved in:
Bibliographic Details
Published in:Biochemical and biophysical research communications 2013-06, Vol.435 (3), p.397-402
Main Authors: He, Xin-yao, Liu, Xian-jin, Chen, Xiao, Bian, Liu-guan, Zhao, Wei-guo, Shen, Jian-kang, Sun, Qing-fang
Format: Article
Language:English
Subjects:
Akt/mTOR signaling and apoptosis
AMP-Activated Protein Kinases - physiology
AMPK
Antineoplastic Agents - pharmacology
Cell Line, Tumor
EGFR
Gambogic acid
Glioblastoma - drug therapy
Glioblastoma - metabolism
Glioblastoma - pathology
Glioma cell
Humans
LRIG1
Mechanistic Target of Rapamycin Complex 1
Membrane Glycoproteins - antagonists & inhibitors
Membrane Glycoproteins - biosynthesis
Membrane Glycoproteins - genetics
Multiprotein Complexes
Proto-Oncogene Proteins c-akt - antagonists & inhibitors
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - metabolism
TOR Serine-Threonine Kinases - antagonists & inhibitors
Tumor Stem Cell Assay
Up-Regulation - drug effects
Xanthones - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:•Gambogic acid induces growth inhibition and apoptosis in cultured U87 glioma cells.•Gambogic acid inhibits Akt/mTORC1 signaling in cultured U87 glioma cells.•LRIG1 induction by gambogic acid promotes EGFR degradation.•AMPK activation mediates gambogic acid-induced LRIG1 upregulation and cytotoxicity. 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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2013.04.099