期刊
CANCER LETTERS
卷 363, 期 1, 页码 46-59出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2015.03.046
关键词
Connexin-43; Low-dose hyper-radiosensitivity; G2/M enrichment; Radiation-induced apoptosis; Differential radiation response
类别
资金
- DRDO - Defence Research and Development Organisation, Ministry of Defence, India [INM-311.1.5]
- University Grants Commission, India
Enrichment of tumour cells in G2/M phases in vitro is known to be associated with low-dose hyper-radiosensitivity (HRS). These cell cycle phases also involve reduced expression of adhesion protein connexin-43 (Cx43). Therefore, we investigated the role of Cx43 in HRS. Asynchronous or G2/M enriched tumour cells (U87, BMG-1, HeLa) and normal primary fibroblasts (HDFn) were gamma-irradiated at varying doses, with an asynchronous group separately subjected to Cx43-knockdown prior to irradiation. Cx43 level, gap junctional activity clonogenic cell survival, cell growth/viability, mitochondrial alterations and other apoptosis-regulating events were studied. G2/M enrichment reduced Cx43 level by similar to 50% and caused considerable HRS at doses 10 cGy-30 cGy in all tumour cell lines. Cx43-knockdown to the same level (similar to 60%) also elicited prominent HRS response in these cells. Quite important, radiosensitivity of primary HDFn cells remained unaltered by all these treatments. In Cx43-knockdown tumour cells, low-dose irradiation caused significant growth inhibition and apoptosis involving loss of MMP, cytochrome-c release and caspase-3 activation, thereby demonstrating the important cytoprotective role of Cx43. Therefore, this study significantly shows that Cx43 downregulation (a constitutive feature of G2/M phase) selectively renders tumour cells hypersensitive to low-dose radiation, and presents connexins as potential therapeutic targets. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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