title: NETRIN-4 protects glioblastoma cells FROM temozolomide induced senescence.
abstract: Glioblastoma multiforme is the most common primary tumor of the central nervous system. The drug temozolomide (TMZ) prolongs lifespan in many glioblastoma patients. The sensitivity of glioblastoma cells to TMZ is interfered by many factors, such as the expression of O-6-methylguanine-DNA methyltransferase (MGMT) and activation of AKT signaling. We have recently identified the interaction between netrin-4 (NTN4) and integrin beta-4 (ITGB4), which promotes glioblastoma cell proliferation via activating AKT-mTOR signaling pathway. In the current work we have explored the effect of NTN4/ITGB4 interaction on TMZ induced glioblastoma cell senescence. We report here that the suppression of either ITGB4 or NTN4 in glioblastoma cell lines significantly enhances cellular senescence. The sensitivity of GBM cells to TMZ was primarily determined by the expression of MGMT. To omit the effect of MGMT, we concentrated on the cell lines devoid of expression of MGMT. NTN4 partially inhibited TMZ induced cell senescence and rescued AKT from dephosphorylation in U251MG cells, a cell line bearing decent levels of ITGB4. However, addition of exogenous NTN4 displayed no significant effect on TMZ induced senescence rescue or AKT activation in U87MG cells, which expressed ITGB4 at low levels. Furthermore, overexpression of ITGB4 combined with exogenous NTN4 significantly attenuated U87MG cell senescence induced by TMZ. These data suggest that NTN4 protects glioblastoma cells from TMZ induced senescence, probably via rescuing TMZ triggered ITGB4 dependent AKT dephosphorylation. This suggests that interfering the interaction between NTN4 and ITGB4 or concomitant use of the inhibitors of the AKT pathway may improve the therapeutic efficiency of TMZ.
authors.affiliation: Departments of Virology and Pathology, Faculty of Medicine, the Haartman Institute, Translational Cancer Biology Research Program and Helsinki University Hospital, University of Helsinki, Helsinki, Finland ; Department of Oncology, the Second Clinical College, Harbin Medical University, Harbin, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Hu
authors.forename: Irene
authors.initials: I
authors.lastname: Ylivinkka
authors.forename: Huini
authors.initials: H
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Jorma
authors.initials: J
authors.lastname: Keski-Oja
authors.forename: Marko
authors.initials: M
authors.lastname: Hyytiäinen
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D039663:Integrin beta4 / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism*; D000075385:Netrins; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077204:Temozolomide
chemical_list: D018906:Antineoplastic Agents, Alkylating; C059834:ITGB4 protein, human; D039663:Integrin beta4; C498815:NTN4 protein, human; D009414:Nerve Growth Factors; D000075385:Netrins; D003606:Dacarbazine; D051057:Proto-Oncogene Proteins c-akt; D000077204:Temozolomide