Department of Biomedical Sciences, College of Medical Science and Technology, Chung Shan Medical University, Taichung, Taiwan.
Int J Cancer. 2013 Oct 15;133(8):1926-35. doi: 10.1002/ijc.28155. Epub 2013 Apr 5.
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.
将具有优先复制能力的细菌用作溶瘤剂是癌症治疗的创新方法之一。当与化疗联合使用时，沙门氏菌在肿瘤内扩散并因此延迟肿瘤生长的能力得到增强。这项工作旨在阐明沙门氏菌和顺铂联合治疗的抗肿瘤作用的潜在机制。功能性缝隙连接的存在对化疗的成功至关重要。在沙门氏菌处理后，观察到连接蛋白 43 (Cx43) 的表达剂量和时间依赖性上调。此外，如荧光染料划痕加载测定所揭示的，沙门氏菌显著增强了细胞间缝隙连接通讯 (GJIC)。为了研究沙门氏菌诱导这些作用的途径，我们发现沙门氏菌诱导了丝裂原激活的蛋白激酶 (MAPK) 信号通路的显著增加。用磷酸化 p38 抑制剂处理细胞可阻止沙门氏菌诱导的 Cx43 上调，但磷酸化细胞外信号调节激酶 (pERK) 抑制剂或磷酸化 c-jun N 末端激酶 (pJNK) 抑制剂则不能。Cx43 的特异性敲低对 GJIC 具有抑制作用，并导致沙门氏菌和顺铂处理后细胞死亡减少。我们的结果表明，沙门氏菌在肿瘤部位的积累导致 Cx43 间隙连接通讯增加，并增强了沙门氏菌和顺铂联合治疗的效果。
