Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication
Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication
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DOI：
10.1007/s00204-012-0963-7
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发表时间：
2013-03-01
影响因子：
6.1
通讯作者：
Vondracek, Jan
中科院分区：
文献类型：
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作者：
Andrysik, Zdenek;Prochazkova, Jirina;Vondracek, Jan
芳香烃受体(AhR)对细胞间的通讯、细胞的黏附、迁移或增殖起着重要的调控作用。在本研究中，我们研究了间隙连接蛋白43(Cx43)和Cx43介导的缝隙连接细胞间通讯(GJIC)在AhR依赖的非肿瘤肝上皮细胞接触抑制中断过程中的调节。细胞增殖的接触性抑制是一个限制融合的未转化细胞的细胞分裂的过程，在癌细胞中经常被取消；然而，导致其破坏的机制仍然只被部分了解。毒性AhR配体2，3，7，8-四氯二苯并对二恶英(TCDD)或多环芳烃对上皮细胞WB-F344的接触抑制被阻断，Cx43蛋白水平降低，可能是通过促进蛋白酶体的降解，显著减少缝隙连接斑块的数量，并以AhR依赖的方式下调GJIC。尽管被TCDD释放的细胞内和细胞膜上的Cx43池都显著减少，但siRNA介导的Cx43基因敲除不足以刺激接触抑制细胞的增殖。我们的数据表明，未转化的上皮细胞中Cx43/GJIC的下调是接触抑制中断的固有部分，接触抑制发生在转录后水平。这一过程与其他形式的细胞间通讯的改变同步进行，从而表明有毒的AhR激动剂可能同时消除接触抑制和减少GJIC，这两个基本机制与肿瘤促进和进展过程中细胞间通讯的解除调控有关。
The aryl hydrocarbon receptor (AhR) contributes to the control of cell-to-cell communication, cell adhesion, migration or proliferation. In the present study, we investigated the regulation of connexin43 (Cx43) and Cx43-mediated gap junctional intercellular communication (GJIC) during the AhR-dependent disruption of contact inhibition in non-tumorigenic liver epithelial cells. The contact inhibition of cell proliferation is a process restricting the cell division of confluent non-transformed cells, which is frequently abolished in cancer cells; however, the mechanisms contributing to its disruption are still only partially understood. Disruption of contact inhibition, which was induced by toxic AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons in epithelial WB-F344 cells, reduced Cx43 protein levels, possibly via enhanced proteasomal degradation, significantly decreased the amount of gap junction plaques and downregulated GJIC, in an AhR-dependent manner. Although both intracellular and membrane Cx43 pools were markedly reduced in cells released from contact inhibition by TCDD, siRNA-mediated Cx43 knock-down was not sufficient to stimulate proliferation in contact-inhibited cells. Our data suggest that downregulation of Cx43/GJIC in non-transformed epithelial cells is an inherent part of disruption of contact inhibition, which occurs at the post-transcriptional level. This process runs in parallel with alterations of other forms of cell-to-cell communication, thus suggesting that toxic AhR agonists may simultaneously abrogate contact inhibition and reduce GJIC, two essential mechanisms linked to deregulation of cell-to-cell communication during tumor promotion and progression.