Gap Junction Intercellular Communication Positively Regulates Cisplatin Toxicity by Inducing DNA Damage through Bystander Signaling.
Gap Junction Intercellular Communication Positively Regulates Cisplatin Toxicity by Inducing DNA Damage through Bystander Signaling.
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DOI：
10.3390/cancers10100368
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发表时间：
2018-10-02
期刊：
影响因子：
5.2
通讯作者：
Patrick SM
中科院分区：
文献类型：
--
作者：
Arora S;Heyza JR;Chalfin EC;Ruch RJ;Patrick SM
辐射诱导的旁观者效应(Ribe)可以以缝隙连接依赖的方式增加未受照射的旁观者细胞的毒性。最近的报道表明，顺铂的毒性也可以通过功能缝隙连接细胞间通讯(GJIC)来介导。在这项使用肺癌和卵巢癌细胞株的研究中，我们证明了顺铂的细胞毒性是由细胞密度介导的。当GJA1或连接蛋白43(Cx43)分别作为缝隙连接基因和蛋白质的靶点时，这种效应就会消失，从而导致顺铂耐药，但仅在高密度或缝隙连接形成密度时才会产生。我们还观察到顺铂介导的旁观者效应是由于DNA双链断裂(DSB)并形成阳性的H_2AX Ser139磷酸化(γH_2AX)，这是DNAD双链断裂的一个指标。当防止形成间隙结时，不会观察到这些DSB。接下来，我们利用顺铂-GG链内加合物特异性抗体，证明顺铂不是穿过缝隙连接的“死亡”信号。最后，我们还发现，缺乏结构特异性DNA内切酶ERCC1-ERCC4(ERCC1-XPF)的细胞，在存在缝隙连接形成密度的情况下，当顺铂处理时，进一步增敏。综上所述，这些结果证明了GJIC在提高顺铂细胞毒性方面的积极作用。
The radiation-induced bystander effect (RIBE) can increase cellular toxicity in a gap junction dependent manner in unirradiated bystander cells. Recent reports have suggested that cisplatin toxicity can also be mediated by functional gap junction intercellular communication (GJIC). In this study using lung and ovarian cancer cell lines, we showed that cisplatin cytotoxicity is mediated by cellular density. This effect is ablated when GJA1 or Connexin 43 (Cx43) is targeted, a gap junction gene and protein, respectively, leading to cisplatin resistance but only at high or gap junction forming density. We also observed that the cisplatin-mediated bystander effect was elicited as DNA Double Strand Breaks (DSBs) with positive H2AX Ser139 phosphorylation (γH2AX) formation, an indicator of DNA DSBs. These DSBs are not observed when gap junction formation is prevented. We next showed that cisplatin is not the “death” signal traversing the gap junctions by utilizing the cisplatin-GG intrastrand adduct specific antibody. Finally, we also showed that cells deficient in the structure-specific DNA endonuclease ERCC1-ERCC4 (ERCC1-XPF), an important mediator of cisplatin resistance, further sensitized when treated with cisplatin in the presence of gap junction forming density. Taken together, these results demonstrate the positive effect of GJIC on increasing cisplatin cytotoxicity.
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DOI：
10.1038/nrc.2016.105
发表时间：
2016-12
期刊：
Nature reviews. Cancer
影响因子：
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作者：
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