Gap junctions propagate opposite effects in normal and tumor testicular cells in response to cisplatin.

Gap junctions propagate toxic effects among tumor cells during chemotherapy, but could also enhance killing of normal cells by the same mechanism. We show that the effect of gap junctional intercellular communication (GJIC) on cisplatin toxicity differs between normal and tumor testicular cells. Downregulation of GJIC by each of several different manipulations (no cell contact, pharmacological inhibition, siRNA suppression) decreased cisplatin cytoxicity in tumor cells but enhanced it in normal cells. Enhanced toxicity due to GJIC downregulation in normal cells correlated with increased DNA interstrand crosslinks. Thus, GJIC protects normal cells from cisplatin toxicity while enhancing it in tumor cells, suggesting that enhancement/maintenance of GJIC increases therapeutic efficacy while decreasing off-target toxicity.