title: Connexin43 confers Temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway.
abstract: Glioblastoma multiforme (GBM) is the most aggressive astrocytoma, and therapeutic options are generally limited to surgical resection, radiotherapy, and Temozolomide (TMZ) chemotherapy. TMZ is a DNA alkylating agent that causes DNA damage and induces cell death. Unfortunately, glioma cells often develop resistance to TMZ treatment, with DNA de-methylation of the MGMT promoter identified as the primary reason. However, the contributions from proteins that normally protect cells against cytotoxic stress in TMZ-induced apoptosis have not been extensively explored. Here, we showed that increasing the level of the gap junction protein, Cx43, in human LN18 and LN229 glioma cells enhances resistance to TMZ treatment while knockdown of Cx43 in these same cells sensitizes them to TMZ treatment. By expressing a channel-dead or a C-terminal truncation mutant of Cx43, we show that Cx43-mediated TMZ resistance involves both channel dependent and independent functions. Expression of Cx43 in LN229 cells decreases TMZ-induced apoptosis, as determined by Annexin V staining. Cx43-mediated chemoresistance appears to be acting via a mitochondrial apoptosis pathway as manifested by the reduction in Bax/Bcl-2 ratio and the release of cytochrome C. Our findings highlight additional mechanisms and proteins that contribute to TMZ resistance, and raise the possibility of increasing TMZ efficiency by targeting Cx43 protein. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'.
authors.affiliation: Department of Cellular and Physiological Science, Life Science Institute, University of British Columbia, 2350 Health Science Mall, Vancouver, BC V6T 1Z3, Canada; Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, Netherlands.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gielen
authors.affiliation: Department of Cellular and Physiological Science, Life Science Institute, University of British Columbia, 2350 Health Science Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Qurratulain
authors.initials: Q
authors.lastname: Aftab
authors.affiliation: Department of Cellular and Physiological Science, Life Science Institute, University of British Columbia, 2350 Health Science Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Noreen
authors.initials: N
authors.lastname: Ma
authors.affiliation: Department of Cellular and Physiological Science, Life Science Institute, University of British Columbia, 2350 Health Science Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Chen
authors.affiliation: Department of Cellular and Physiological Science, Life Science Institute, University of British Columbia, 2350 Health Science Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Hong
authors.affiliation: Department of Cellular and Physiological Science, Life Science Institute, University of British Columbia, 2350 Health Science Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Shannon
authors.initials: S
authors.lastname: Lozinsky
authors.affiliation: Department of Cellular and Physiological Science, Life Science Institute, University of British Columbia, 2350 Health Science Mall, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Naus
authors.affiliation: Department of Cellular and Physiological Science, Life Science Institute, University of British Columbia, 2350 Health Science Mall, Vancouver, BC V6T 1Z3, Canada. Electronic address: cnaus@mail.ubc.ca.
authors.forename: Wun Chey
authors.initials: WC
authors.lastname: Sin
mesh_terms: D000704:Analysis of Variance; D017304:Annexin A5 / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000378:metabolism; D005910:Glioma / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D000077204:Temozolomide; D013997:Time Factors; D014162:Transfection
chemical_list: D017304:Annexin A5; D018906:Antineoplastic Agents, Alkylating; D018031:Connexin 43; D005452:Fluoresceins; D034741:RNA, Small Interfering; D003606:Dacarbazine; D045304:Cytochromes c; C007740:fluorexon; D000077204:Temozolomide
keywords: Cx43; Cytochrome C; Glioma; TMZ