Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation.
Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation.
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DOI：
10.1371/journal.pone.0127498
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Solomon JM
中科院分区：
文献类型：
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作者：
Carson C;Raman P;Tullai J;Xu L;Henault M;Thomas E;Yeola S;Lao J;McPate M;Verkuyl JM;Marsh G;Sarber J;Amaral A;Bailey S;Lubicka D;Pham H;Miranda N;Ding J;Tang HM;Ju H;Tranter P;Ji N;Krastel P;Jain RK;Schumacher AM;Loureiro JJ;George E;Berellini G;Ross NT;Bushell SM;Erdemli G;Solomon JM
Engerin A是一种结构独特的天然产物，据报道可以选择性地抑制肾癌细胞系的生长。对500多个具有良好特征的癌细胞株进行的大规模表型细胞图谱实验(CLIP)表明，Enlerin A抑制来自许多谱系的肿瘤细胞亚群的生长，而不仅仅是肾细胞癌。TRPC4阳离子通道的表达是与Englerin A敏感性最相关的细胞系特征，这表明TRPC4是englerin A的疗效靶点的假设。遗传实验表明，TRPC4的表达对于englerin A诱导的生长抑制既是必要的，也是充分的。Engerin A诱导高水平TRPC4或其近邻同源基因TRPC5表达的细胞内钙内流和膜去极化。电生理实验证实，Englerin A是TRPC4激动剂。TRPC4/C5抑制剂ML204可阻断Englerin A诱导的电流和Englerin A诱导的生长抑制。这些实验证实了TRPC4/C5通道的激活抑制了肿瘤细胞系的增殖，并证实了细胞系图谱所产生的TRPC4靶点假说。在选择性分析中，Enlerin A对TRPA1、TRPV3/V4和TRPM8有微弱的抑制作用，这表明Enlerin A可能结合了Trp离子通道的一个共同特征。活体实验表明，在接近激活TRPC4通道所需剂量的情况下，Englerin A对啮齿动物是致命的。这种毒性表明英格列林A本身可能不适合进一步的药物开发。然而，由于Enlerin A可以在实验室中合成，它可能是一个有用的化学起点，以确定其他Trp家族通道的新调节剂。
Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of englerin A on ¬over 500 well characterized cancer cell lines showed that englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for englerin A. Genetic experiments demonstrate that TRPC4 expression is both necessary and sufficient for englerin A induced growth inhibition. Englerin A induces calcium influx and membrane depolarization in cells expressing high levels of TRPC4 or its close ortholog TRPC5. Electrophysiology experiments confirmed that englerin A is a TRPC4 agonist. Both the englerin A induced current and the englerin A induced growth inhibition can be blocked by the TRPC4/C5 inhibitor ML204. These experiments confirm that activation of TRPC4/C5 channels inhibits tumor cell line proliferation and confirms the TRPC4 target hypothesis generated by the cell line profiling. In selectivity assays englerin A weakly inhibits TRPA1, TRPV3/V4, and TRPM8 which suggests that englerin A may bind a common feature of TRP ion channels. In vivo experiments show that englerin A is lethal in rodents near doses needed to activate the TRPC4 channel. This toxicity suggests that englerin A itself is probably unsuitable for further drug development. However, since englerin A can be synthesized in the laboratory, it may be a useful chemical starting point to identify novel modulators of other TRP family channels.
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DOI：
10.1002/anie.201411511
发表时间：
2015-03-16
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Akbulut Y;Gaunt HJ;Muraki K;Ludlow MJ;Amer MS;Bruns A;Vasudev NS;Radtke L;Willot M;Hahn S;Seitz T;Ziegler S;Christmann M;Beech DJ;Waldmann H
通讯作者：
Waldmann H
影响因子：
5.2
作者：
Ratnayake, Ranjala;Covell, David;Ransom, Tanya T.;Gustafson, Kirk R.;Beutler, John A.
通讯作者：
Beutler, John A.
影响因子：
7.3
作者：
Rooney, Lisa;Vidal, Agnes;Tully, David C.
通讯作者：
Tully, David C.
影响因子：
64.5
作者：
Riccio A;Li Y;Moon J;Kim KS;Smith KS;Rudolph U;Gapon S;Yao GL;Tsvetkov E;Rodig SJ;Van't Veer A;Meloni EG;Carlezon WA Jr;Bolshakov VY;Clapham DE
通讯作者：
Clapham DE
TRP通道的结构生物学。
影响因子：
--
作者：
Li, Minghui;Yu, Yong;Yang, Jian
通讯作者：
Yang, Jian