Inhibition of TRPC6 reduces non-small cell lung cancer cell proliferation and invasion.
Inhibition of TRPC6 reduces non-small cell lung cancer cell proliferation and invasion.
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抑制 TRPC6 可减少非小细胞肺癌细胞增殖和侵袭
DOI：
10.18632/oncotarget.14034
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发表时间：
2017-01-17
期刊：
影响因子：
--
通讯作者：
Ma HP
中科院分区：
文献类型：
--
作者：
Yang LL;Liu BC;Lu XY;Yan Y;Zhai YJ;Bao Q;Doetsch PW;Deng X;Thai TL;Alli AA;Eaton DC;Shen BZ;Ma HP
最近的研究表明，瞬时受体电位规范6 （transient receptor potential canonical 6, TRPC6）通道在几种类型的癌细胞中高度表达。然而，TRPC6是否与人类非小细胞肺癌（NSCLC）的恶性发展有关尚不清楚。我们以人NSCLC A549细胞系为模型，发现药物阻断或分子敲低TRPC6通道通过阻断S-G2M期细胞周期抑制A549细胞的增殖，导致相当一部分细胞分离和聚集，但未诱导任何类型的细胞死亡。Western blot和细胞周期分析显示，S-G2M期离体的圆形细胞比G1期仍贴体的多边形细胞表达更多的TRPC6。膜片钳数据还显示，离体细胞的TRPC全细胞电流明显高于未离体细胞。Ca2+渗透性TRPC6通道的抑制显著降低了A549细胞内的Ca2+。有趣的是，无论是阻断还是敲低TRPC6，都能显著降低这种NSCLC细胞系的侵袭，并降低附着蛋白、纤维连接蛋白和紧密连接蛋白、小带闭塞蛋白-1 （ZO-1）的表达。这些数据表明，TRPC6介导的细胞内Ca2+升高通过促进细胞周期进展刺激NSCLC细胞增殖，抑制TRPC6可减弱细胞增殖和侵袭。因此，进一步的体内研究可能会导致考虑使用特异性TRPC6阻滞剂作为治疗NSCLC的补充。
Recent studies indicate that the transient receptor potential canonical 6 (TRPC6) channel is highly expressed in several types of cancer cells. However, it remains unclear whether TRPC6 contributes to the malignancy of human non-small cell lung cancer (NSCLC). We used a human NSCLC A549 cell line as a model and found that pharmacological blockade or molecular knockdown of TRPC6 channel inhibited A549 cell proliferation by arresting cell cycle at the S-G2M phase and caused a significant portion of cells detached and rounded-up, but did not induce any types of cell death. Western blot and cell cycle analysis show that the detached round cells at the S-G2M phase expressed more TRPC6 than the still attached polygon cells at the G1 phase. Patch-clamp data also show that TRPC whole-cell currents in the detached cells were significantly higher than in the still attached cells. Inhibition of Ca2+-permeable TRPC6 channels significantly reduced intracellular Ca2+ in A549 cells. Interestingly, either blockade or knockdown of TRPC6 strongly reduced the invasion of this NSCLC cell line and decreased the expression of an adherent protein, fibronectin, and a tight junction protein, zonula occluden protein-1 (ZO-1). These data suggest that TRPC6-mediated elevation of intracellular Ca2+ stimulates NSCLC cell proliferation by promoting cell cycle progression and that inhibition of TRPC6 attenuates cell proliferation and invasion. Therefore, further in vivo studies may lead to a consideration of using a specific TRPC6 blocker as a complement to treat NSCLC.