Abstract
The radiation-induced bystander effect (RIBE) can increase cellular toxicity in a gap junction dependent manner in unirradiated bystander cells. Recent reports have suggested that cisplatin toxicity can also be mediated by functional gap junction intercellular communication (GJIC). In this study using lung and ovarian cancer cell lines, we showed that cisplatin cytotoxicity is mediated by cellular density. This effect is ablated when GJA1 or Connexin 43 (Cx43) is targeted, a gap junction gene and protein, respectively, leading to cisplatin resistance but only at high or gap junction forming density. We also observed that the cisplatin-mediated bystander effect was elicited as DNA Double Strand Breaks (DSBs) with positive H2AX Ser139 phosphorylation (γH2AX) formation, an indicator of DNA DSBs. These DSBs are not observed when gap junction formation is prevented. We next showed that cisplatin is not the “death” signal traversing the gap junctions by utilizing the cisplatin-GG intrastrand adduct specific antibody. Finally, we also showed that cells deficient in the structure-specific DNA endonuclease ERCC1-ERCC4 (ERCC1-XPF), an important mediator of cisplatin resistance, further sensitized when treated with cisplatin in the presence of gap junction forming density. Taken together, these results demonstrate the positive effect of GJIC on increasing cisplatin cytotoxicity.
Highlights
Cisplatin chemotherapy is effective and currently active against tumor types from various ontogenies, including osteosarcomas, testicular, lung, ovarian, cervical and head and neck cancers [1,2].Since its discovery by Rosenberg as a potential chemotherapeutic agent nearly 50 years ago, many groups have worked on assessing cisplatin’s mechanism of action
Lung and ovarian cancer cell lines were tested for density dependent cisplatin cytotoxicity
It has been shown that a high-density confluent monolayer of cells promotes the formation of gap junctions (GJs) while at low colony forming density cells are dispersed with no contact to promote GJ formation
Summary
Cisplatin chemotherapy is effective and currently active against tumor types from various ontogenies, including osteosarcomas, testicular, lung, ovarian, cervical and head and neck cancers [1,2].Since its discovery by Rosenberg as a potential chemotherapeutic agent nearly 50 years ago, many groups have worked on assessing cisplatin’s mechanism of action. Cisplatin chemotherapy is effective and currently active against tumor types from various ontogenies, including osteosarcomas, testicular, lung, ovarian, cervical and head and neck cancers [1,2]. Cisplatin reacts with DNA to produce platinum-DNA adducts, including intraand inter-strand crosslinks (ICLs), and it is well accepted that these lesions mediate cisplatin’s cytotoxic effect [3]. It is well known that resistance to cisplatin and its analogues can arise through multiple mechanisms broadly divided into: (1) Mechanisms that reduced the formation of platinum-DNA adducts such as decreased drug uptake, increased drug efflux, detoxification, or increased/altered. Work by Jensen and Glazer has shown that cisplatin treatment could lead to cytotoxicity in neighboring untreated bystander cells through gap junctions (GJs) [5]. More recent studies have focused on the role of Cx43 in mediating the bystander effect after cisplatin treatment
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