Enhanced effect of connexin 43 on cisplatin-induced cytotoxicity in mesothelioma cells.
Enhanced effect of connexin 43 on cisplatin-induced cytotoxicity in mesothelioma cells.
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DOI：
10.1254/jphs.08327fp
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发表时间：
2009
影响因子：
3.5
通讯作者：
Hiromi Sato;H. Iwata;Y. Takano;Ryota Yamada;H. Okuzawa;Y. Nagashima;K. Yamaura;K. Ueno;T. Yano
中科院分区：
文献类型：
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作者：
Hiromi Sato;H. Iwata;Y. Takano;Ryota Yamada;H. Okuzawa;Y. Nagashima;K. Yamaura;K. Ueno;T. Yano
作为间隙连接（GJ）组分的连接蛋白（Cx）蛋白的表达水平在许多癌症中经常降低，并且已经显示恢复其水平具有抗肿瘤作用。以前，已经在几种恶性间皮瘤（malignant mesothelioma，NHL）中观察到细胞间缝隙连接通讯（gap junctional intercellular communication，GJIC）功能障碍，并且在许多Cx蛋白中，Cx43在非致瘤性间皮瘤组织中显著表达。因此，我们研究了Cx43上调是否对MM细胞系（H28细胞）具有抗肿瘤作用，特别是关于耐药性。化疗药物顺铂（CDDP）治疗后，MM细胞活力显着下降，并观察到Cx43转染克隆的凋亡诱导。特异性GJIC抑制剂不能消除这种作用。另一方面，已知Src蛋白磷酸化Cx43，这导致GJIC抑制。这表明Src活性也可能受到Cx43过表达的调节。事实上，Src蛋白水平在Cx43转染的克隆中降低。此外，Src抑制增强CDDP在亲本H28细胞中的细胞毒性。这些数据表明，Cx43可以提高耐CDDP在GJIC非依赖性的方式，这可能是部分通过抑制Src活性介导的。
The expression levels of connexin (Cx) proteins, which are gap junction (GJ) components, are often decreased in many cancers, and restoring their levels has been shown to have antitumor effects. Previously, dysfunctional gap junctional intercellular communication (GJIC) has been observed in several malignant mesotheliomas (MMs), and among the many Cx proteins, Cx43 is prominently expressed in nontumorigenic mesothelial tissues. Therefore, we investigated whether Cx43 upregulation has an antitumor effect on an MM cell line (H28 cell), especially with regard to drug resistance. After treatment with the chemotherapeutic agent cisplatin (CDDP), MM cell viability significantly decreased, and apoptosis induction was observed in Cx43-transfected clones. A specific GJIC inhibitor could not abrogate this effect. On the other hand, the Src protein is known to phosphorylate Cx43, which results in GJIC inhibition. This suggests that Src activity might also be regulated by the hyperexpression of Cx43. In fact, the Src protein level was decreased in Cx43-transfected clones. Moreover, Src inhibition reinforced CDDP cytotoxicity in parental H28 cells. These data suggest that Cx43 could improve the resistance to CDDP in a GJIC-independent manner, which may be partly mediated by the suppression of Src activity.