title: Different gap junction-propagated effects on cisplatin transfer result in opposite responses to cisplatin in normal cells versus tumor cells.
abstract: Previous work has shown that gap junction intercellular 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). The downregulation of GJIC by several different manipulations (no cell contact, pharmacological inhibition, and siRNA suppression) decreased Pt toxicity in tumor cells but enhanced it in non-tumor cells. 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. The intracellular Pt and DNA-Pt adduct contents clearly increased in non-tumor cells but decreased in tumor cells when GJIC was downregulated. Further 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. Thus, GJIC protects normal organs from cisplatin toxicity while enhancing it in tumor cells via its different effects on intracellular Pt transfer.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tao
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Fan
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China.
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China.
authors.forename: Kefan
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People's Republic of China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000493:pharmacokinetics*; D017629:Gap Junctions / Q000502:physiology*; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin