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Connexin43 confers Temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway.
- Source :
-
Neuropharmacology [Neuropharmacology] 2013 Dec; Vol. 75, pp. 539-48. Date of Electronic Publication: 2013 May 18. - Publication Year :
- 2013
-
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'.<br /> (Copyright © 2013. Published by Elsevier Ltd.)
- Subjects :
- Analysis of Variance
Annexin A5 metabolism
Brain Neoplasms metabolism
Cell Line, Tumor
Connexin 43 genetics
Cytochromes c metabolism
Dacarbazine pharmacology
Dose-Response Relationship, Drug
Fluoresceins metabolism
Glioma metabolism
Humans
Mitochondria drug effects
Mutation
Phosphorylation drug effects
RNA, Small Interfering pharmacology
Temozolomide
Time Factors
Transfection
Antineoplastic Agents, Alkylating pharmacology
Apoptosis drug effects
Connexin 43 metabolism
Dacarbazine analogs & derivatives
Mitochondria pathology
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 75
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 23688923
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2013.05.002