OBJECTIVE Previous work has shown that gap junction intercel ular communication(GJIC)enhances cisplatin(Pt)toxicity in testicular tumor cells but decreases it in non-tumor testicular cells.In this study,these different GJIC-propagated effects were demonstrated in tumor versus non-tumor cells from other organ tissues(liver and lung).METHODS We use several different mani pulations(no cell contact,pharmacological inhibition,and si RNA suppression)to down-regulate GJIC function.The in vivo results using xenograft tumor models were consistent with those from the above-mentioned cells.To better understand the mechanism(s)involved,we studied the effects of GJIC on Pt accumulation in tumor and non-tumor cells from the liver and lung.RESULTS The intracel ular Pt and DNA-Pt adduct contents clearly increased in non-tumor cells but decreasedin tumor cells when GJIC was downregulated.Further analysis indicated that the opposite effectsof GJIC on Pt accumulation in normal versus tumor cells from the liver were due to its different effects on copper transporter1 and multidrug resistance-associated protein2,membrane transporters attributed to intracellular Pt transfer.CONCLUSION GJIC protects normal organs from cisplatin toxicity while enhancing it in tumor cells via its different effects on intracellular Pt transfer. OBJECTIVE Previous work has shown that gap junction intercellar communication (GJIC) enhances cisplatin (Pt) toxicity in testicular tumor cells but keeps it in non-tumor testicular cells. In this study, these different GJIC-propagated effects were demonstrated in tumor versus non -tumor cells from other organ tissues (liver and lung). METHODS We use several different mani pulations (no cell contact, pharmacological inhibition, and si RNA suppression) to down-regulate GJIC function.The in vivo results using xenograft tumor models were consistent with those from the above-mentioned cells. To better understand the mechanism (s) involved, we studied the effects of GJIC on Pt accumulation in tumor and non-tumor cells from the liver and lung .RESULTS The intracellar Pt and DNA-Pt adduct contents clearly increased in non-tumor cells but decreased in tumor cells when GJIC was downregulated. Future analysis indicated that the opposite effects of GJIC on Pt accumulation in normal versus tumor cells from the liver were due to its different effects on copper transporter1 and multidrug resistance-associated protein2, membrane transporters attributed to intracellular Pt transfer. CONCLUSION GJIC protects normal organs from cisplatin toxicity while enhancing it in tumor cells via its different effects on intracellular Pt transfer.