Abstract
The gap junction (GJ) protein connexin-43 (Cx43) is considered as a tumour suppressor protein for its role in reversing the phenotype of the cancer cells. In this study, we exploited the antitumor property of Cx43 in conjunction with the artesunate (ART), a plant-based active anti-malarial compound. The reactive oxygen species (ROS) generated by ART resulted in DNA damage, which in turn led to DNA damage response by activation of DNA damage repair proteins. GJ deficient MCF-7 cells transfected with Cx43 gene showed an increased sensitivity towards dose-dependent ART treatment and required a significantly lower dose of ART to attain its IC50, as compared to parental cells. This would ultimately result in reduced dose-dependent side effects of ART. The Co-culture experiments involving GJ intercellular communication (GJIC) deficient and GJIC enabled cells, established the transfer of ROS to the neighbouring cancer cells not exposed to ART. The ROS accumulated in the ART-treated cells induced the oxidative damage in neighbouring cells, leading to bystander cell death and inhibition of bystander cell proliferation. Thus, our study revealed that expression of Cx43 helped in reducing the dose-dependent cytotoxicity of ART as well as enhanced the bystander apoptosis of the neighbouring cells.
Highlights
Gap junctions (GJs) are the fundamental entities for intercellular communications that contribute to cell differentiation, maintenance of normal cell growth, embryonic development, and tissue homeostasis[1, 2]
The relative expression analysis of Cx43 in MCF7 and Cx43-MCF7 cells showed the 157-fold increase expression in MCF7 and Cx43-MCF7 cells were analysed by using real-time polymerase chain reaction (PCR)
Lack of GJ intercellular communication (GJIC) is more often found in various human tumours compared with adjacent normal tissues
Summary
Gap junctions (GJs) are the fundamental entities for intercellular communications that contribute to cell differentiation, maintenance of normal cell growth, embryonic development, and tissue homeostasis[1, 2]. Understanding the intricate association between GJs and cancer may shed considerable light on possible modes of cancer therapy. The tumour suppressive activity of Cx43 is limited to the exchange of specific molecules between normal cells and the tumour cells, but in some cases has been found to be via GJ independent pathways[6,7,8,9]. GJ dependent mechanism of Cx43 helps in the spreading of prodrug (bystander effect)[10] as well as small regulating signalling molecules in the neighbouring cells. The GJIC established between the neighbouring cells helped in the bystander killing of the cells after ART treatment. We provided evidences in favour of the contribution of ROS generated by ART, in suppressing the growth of the neighbouring cells
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