title: TMZ-induced PrPc/par-4 interaction promotes the survival of human glioma cells.
abstract: Malignant gliomas recur even after extensive surgery and chemo-radiotherapy. Although a relatively novel chemotherapeutic agent, temozolomide (TMZ), has demonstrated promising activity against gliomas, the effects last only a few months and drug resistance develops thereafter in many cases. It has been acknowledged that glioma cells respond to TMZ treatment by undergoing G2/M arrest, but not apoptosis. Here we demonstrate a phase-specific chemotherapy resistance due to cellular prion protein (PrPc) in human glioma cells upon TMZ treatment. TMZ-induced G2/M-arrested cultures show an upregulation of PrPc expression and are more resistant, whereas G1/S-phase cells that show decreased levels of PrPc are more sensitive to apoptosis. Furthermore, an investigation into the biological significance of PrPc association with par-4 provided the first evidence of a relationship between the endogenous levels of PrPc and the resistance of glioma cells to the apoptotic effects of TMZ. Upon TMZ treatment, PrPc exerts its antiapoptotic activity by inhibiting PKA-mediated par-4 phosphorylation that are important for par-4 activation, nuclear entry and initiation of apoptosis. In context with cell cycle-dependent responses to chemotherapy, the data from this study suggest the possibility of exploiting the PrPc-dependent pathway to improve the efficacy of TMZ-based regimen for patients with gliomas.
authors.affiliation: Department of Neurosurgery, HuaShan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Dongxiao
authors.initials: D
authors.lastname: Zhuang
authors.forename: Yingchao
authors.initials: Y
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Mao
authors.forename: Liang
authors.initials: L
authors.lastname: Gao
authors.forename: Haishi
authors.initials: H
authors.lastname: Zhang
authors.forename: Shihai
authors.initials: S
authors.lastname: Luan
authors.forename: Fengping
authors.initials: F
authors.lastname: Huang
authors.forename: Qingquan
authors.initials: Q
authors.lastname: Li
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010766:Phosphorylation; D018621:PrPC Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000077204:Temozolomide; D014162:Transfection
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018621:PrPC Proteins; D034741:RNA, Small Interfering; D018179:Receptors, Thrombin; D003606:Dacarbazine; D017868:Cyclic AMP-Dependent Protein Kinases; C112908:protease-activated receptor 4; D000077204:Temozolomide