title: Salmonella enhance chemosensitivity in tumor through connexin 43 upregulation.
abstract: The use of preferentially replicating bacteria as oncolytic agents is one of the innovative approaches for the treatment of cancer. The capability of Salmonella to disperse within tumors and hence to delay tumor growth was augmented when combined with chemotherapy. This work is warranted to elucidate the underlying mechanism of antitumor effects by the combination therapy of Salmonella and cisplatin. The presence of functional gap junctions is highly relevant for the success of chemotherapy. Following Salmonella treatment, dose- and time-dependent upregulation of connexin 43 (Cx43) expressions were observed. Moreover, Salmonella significantly enhanced gap intercellular communication (GJIC), as revealed by the fluorescent dye scrape loading assay. To study the pathway underlying these Salmonella-induced effects, we found that Salmonella induced a significant increase in mitogen-activated protein kinases (MAPK) signaling pathways. The Salmonella-induced upregulation of Cx43 was prevented by treatment of cells with the phosphorylated p38 inhibitor, but not phosphorylated extracellular signal-regulated kinase (pERK) inhibitor or phosphorylated c-jun N terminal kinase (pJNK) inhibitor. Specific knockdown of Cx43 had an inhibitory effect on GJIC and resulted in a reduction of cell death after Salmonella and cisplatin treatment. Our results suggest that accumulation of Salmonella in tumor sites leads to increase Cx43 gap junction communication and enhances the combination of Salmonella and cisplatin therapeutic effects.
authors.affiliation: Department of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Chang
authors.forename: Chih-Ho
authors.initials: CH
authors.lastname: Lai
authors.forename: Man-Chin
authors.initials: MC
authors.lastname: Chen
authors.forename: Chi-Fan
authors.initials: CF
authors.lastname: Liu
authors.forename: Yu-Diao
authors.initials: YD
authors.lastname: Kuan
authors.forename: Song-Tao
authors.initials: ST
authors.lastname: Lin
authors.forename: Che-Hsin
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001691:Biological Therapy; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000382:microbiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D012475:Salmonella / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D018031:Connexin 43; D004791:Enzyme Inhibitors; D005419:Flavonoids; C543076:GJA1 protein, mouse; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D002945:Cisplatin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: cisplatin; gap junctions, connexin 43, Salmonella; tumor