Timucin Avsar1,2, Tansu Bilge Kose3, Muhammed Deniz Oksal3, Gizem Turan3, Turker Kilic3,4. 1. School of Medicine, Medical Biology Department, Bahcesehir University, Istanbul, Turkey. timucin.avsar@med.bau.edu.tr. 2. Graduate School, Neuroscience Program, Bahcesehir University, Istanbul, Turkey. timucin.avsar@med.bau.edu.tr. 3. Graduate School, Neuroscience Program, Bahcesehir University, Istanbul, Turkey. 4. School of Medicine, Neurosurgery Department, Bahcesehir University, Istanbul, Turkey.
Abstract
BACKGROUND: Glioma is the most common type of brain tumors and isocitrate dehydrogenase (IDH1) gene is the most prominent molecular marker about the disease prognosis, response to therapy and patient survival. There are conflicting data about the effect of IDH1 mutation on glial cell proliferation, invasion and migration characteristics. The effect of IDH1 mutation on mTOR signaling pathway, which has key roles in tumorigenesis process, is limited and previous data is controversial. We aimed to explore the effect of wild type and mutant IDH1 overexpression on glioma cells and investigated the correlation with mTOR signaling pathway associated genes. METHODS AND RESULTS: U87-MG and A172 cells were transfected with different IDH1 mutant gene overexpressing (R132H, R132L, R132S, R132C) viral vectors. Cell proliferation, cell invasion and migration analysis as well as quantitative PCR analysis with the mutant glioma cell lines were performed. Forty-two patient derived glioma cells were obtained from patients with different glioma subtypes and cancer cells were enriched by culturing cells. Overexpression of both mutant and wild type IDH1 gene promoted the cell proliferation, but only IDH1 mutation increased cell invasion and migration. The expression of IDH1 mutation activated mTOR signaling via upregulation of WNTA, PRKAA2, GSK3B and MTOR genes as well as phosphorylated mTOR protein level. CONCLUSIONS: Our results highlighted IDH1 mutation upregulate mTOR signaling pathway and promote cell proliferation, invasion and migration.
BACKGROUND: Glioma is the most common type of brain tumors and isocitrate dehydrogenase (IDH1) gene is the most prominent molecular marker about the disease prognosis, response to therapy and patient survival. There are conflicting data about the effect of IDH1 mutation on glial cell proliferation, invasion and migration characteristics. The effect of IDH1 mutation on mTOR signaling pathway, which has key roles in tumorigenesis process, is limited and previous data is controversial. We aimed to explore the effect of wild type and mutant IDH1 overexpression on glioma cells and investigated the correlation with mTOR signaling pathway associated genes. METHODS AND RESULTS: U87-MG and A172 cells were transfected with different IDH1 mutant gene overexpressing (R132H, R132L, R132S, R132C) viral vectors. Cell proliferation, cell invasion and migration analysis as well as quantitative PCR analysis with the mutant glioma cell lines were performed. Forty-two patient derived glioma cells were obtained from patients with different glioma subtypes and cancer cells were enriched by culturing cells. Overexpression of both mutant and wild type IDH1 gene promoted the cell proliferation, but only IDH1 mutation increased cell invasion and migration. The expression of IDH1 mutation activated mTOR signaling via upregulation of WNTA, PRKAA2, GSK3B and MTOR genes as well as phosphorylated mTOR protein level. CONCLUSIONS: Our results highlighted IDH1 mutation upregulate mTOR signaling pathway and promote cell proliferation, invasion and migration.
Authors: Christian Hartmann; Jochen Meyer; Jörg Balss; David Capper; Wolf Mueller; Arne Christians; Jörg Felsberg; Marietta Wolter; Christian Mawrin; Wolfgang Wick; Michael Weller; Christel Herold-Mende; Andreas Unterberg; Judith W M Jeuken; Peter Wesseling; Guido Reifenberger; Andreas von Deimling Journal: Acta Neuropathol Date: 2009-06-25 Impact factor: 17.088
Authors: Alexandra R Grassian; Seth J Parker; Shawn M Davidson; Ajit S Divakaruni; Courtney R Green; Xiamei Zhang; Kelly L Slocum; Minying Pu; Fallon Lin; Chad Vickers; Carol Joud-Caldwell; Franklin Chung; Hong Yin; Erika D Handly; Christopher Straub; Joseph D Growney; Matthew G Vander Heiden; Anne N Murphy; Raymond Pagliarini; Christian M Metallo Journal: Cancer Res Date: 2014-04-22 Impact factor: 13.312
Authors: David N Louis; Arie Perry; Pieter Wesseling; Daniel J Brat; Ian A Cree; Dominique Figarella-Branger; Cynthia Hawkins; H K Ng; Stefan M Pfister; Guido Reifenberger; Riccardo Soffietti; Andreas von Deimling; David W Ellison Journal: Neuro Oncol Date: 2021-08-02 Impact factor: 13.029