title: LRIG1 dictates the chemo-sensitivity of temozolomide (TMZ) in U251 glioblastoma cells via down-regulation of EGFR/topoisomerase-2/Bcl-2.
abstract: In the current study, we aimed to understand the potential role of leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) in TMZ-resistance of U251 glioma cells. We established TMZ-resistant U251 clones (U251/TMZ cells), which expressed low level of LRIG1, but high levels of epidermal growth factor receptor (EGFR), topoisomerase-2 (Topo-2) and Bcl-2. Depletion of LRIG1 by the targeted RNA interference (RNAi) upregulated EGFR/Topo-2/Bcl-2 in U251 cells, and the cells were resistant to TMZ. Reversely, over-expression of LRIG1 in U251 cells downregulated EGFR/Topo-2/Bcl-2 expressions, and cells were hyper-sensitive to TMZ. Our data suggested EGFR-dependent mammalian target of rapamycin (mTOR) activation was important for Topo-2 and Bcl-2 expressions in U251/TMZ cells. The EGFR inhibitor and the mTOR inhibitor downregulated Topo-2/Bcl-2 expressions, both inhibitors also restored TMZ sensitivity in U251/TMZ cells. Finally, inhibition of Topo-2 or Bcl-2 by targeted RNAi(s) knockdown or by the corresponding inhibitor re-sensitized U251/TMZ cells to TMZ, indicating that both Topo-2 and Bcl-2 were important for TMZ resistance in the resistant U251 cells. Based on these results, we concluded that LRIG1 inhibits EGFR expression and the downstream signaling activation, interferes with Bcl-2/Topo-2 expressions and eventually sensitizes glioma cells to TMZ.
authors.affiliation: Department of Neurosurgery, Sir Run Run Shaw Hospital, College of Medical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Xu-chen
authors.initials: XC
authors.lastname: Qi
authors.forename: Da-jiang
authors.initials: DJ
authors.lastname: Xie
authors.forename: Qing-feng
authors.initials: QF
authors.lastname: Yan
authors.forename: Yi-rong
authors.initials: YR
authors.lastname: Wang
authors.forename: Yin-xin
authors.initials: YX
authors.lastname: Zhu
authors.forename: Cong
authors.initials: C
authors.lastname: Qian
authors.forename: Shu-xu
authors.initials: SX
authors.lastname: Yang
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034622:RNA Interference; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D003606:Dacarbazine; D066246:ErbB Receptors; D004250:DNA Topoisomerases, Type II; D000077204:Temozolomide
keywords: , leucine-rich repeats and immunoglobulin-like domains 1; Bcl-2; EGFR; Epidermal growth factor receptor; GBM; Glioblastoma; LRIG1; PI3K; RNAi RNA interference; TMZ; Temozolomide; Topo-2; Topoisomerase-2; glioblastoma multiforme; mTOR; mammalian target of rapamycin; phosphatidylinositol 3-kinase; temozolomide; topoisomerase-2