Na(+) entry through heteromeric TRPC4/C1 channels mediates (-)Englerin A-induced cytotoxicity in synovial sarcoma cells.
Na(+) entry through heteromeric TRPC4/C1 channels mediates (-)Englerin A-induced cytotoxicity in synovial sarcoma cells.
复制标题
DOI：
10.1038/s41598-017-17303-3
复制
发表时间：
2017-12-05
影响因子：
4.6
通讯作者：
Beech DJ
中科院分区：
文献类型：
--
作者：
Muraki K;Ohnishi K;Takezawa A;Suzuki H;Hatano N;Muraki Y;Hamzah N;Foster R;Waldmann H;Nussbaumer P;Christmann M;Bon RS;Beech DJ
倍半萜(−)恩格列菌素A(EA)是叶下珠中的一种有机化合物，它通过异构体TRPC4/C1通道对某些类型的癌细胞产生细胞毒作用，而对正常细胞不产生细胞毒作用。在此，我们鉴定了EA对人滑膜肉瘤细胞(SW982细胞)的选择性细胞毒性，并探讨了其作用机制。电针诱导的SW982细胞阳离子通道电流(ICAT)具有异构体TRPC4/C1通道的生物物理特性。同源TRPC4通道的抑制剂是ICAT和EA诱导的细胞毒性的弱抑制剂，而TRPC4/C1通道的强效抑制剂(Pico145)则强烈地抑制ICAT和细胞毒性。耗竭TRPC1使ICAT产生具有同质TRPC4通道生物物理和药理特性的电流，耗竭TRPC1或TRPC4可抑制EA的细胞毒作用。Na+/K+-ATPase抑制剂哇巴因增强了电针的细胞毒作用，在没有电针的情况下，革兰菌素A直接的Na+负荷引起了Pico145抗性的细胞毒。结论：电针对人滑膜肉瘤细胞具有较强的细胞毒作用，其作用机制可能与异构体TRPC4/C1通道和钠离子负荷有关。
The sesquiterpene (−)Englerin A (EA) is an organic compound from the plant Phyllanthus engleri which acts via heteromeric TRPC4/C1 channels to cause cytotoxicity in some types of cancer cell but not normal cells. Here we identified selective cytotoxicity of EA in human synovial sarcoma cells (SW982 cells) and investigated the mechanism. EA induced cation channel current (Icat) in SW982 cells with biophysical characteristics of heteromeric TRPC4/C1 channels. Inhibitors of homomeric TRPC4 channels were weak inhibitors of the Icat and EA-induced cytotoxicity whereas a potent inhibitor of TRPC4/C1 channels (Pico145) strongly inhibited Icat and cytotoxicity. Depletion of TRPC1 converted Icat into a current with biophysical and pharmacological properties of homomeric TRPC4 channels and depletion of TRPC1 or TRPC4 suppressed the cytotoxicity of EA. A Na+/K+-ATPase inhibitor (ouabain) potentiated EA-induced cytotoxicity and direct Na+ loading by gramicidin-A caused Pico145-resistant cytotoxicity in the absence of EA. We conclude that EA has a potent cytotoxic effect on human synovial sarcoma cells which is mediated by heteromeric TRPC4/C1 channels and Na+ loading.
登录
查看更多内容
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：
--
作者：
Sourbier C;Scroggins BT;Mannes PZ;Liao PJ;Siems K;Wolf D;Beutler JA;Linehan WM;Neckers L
通讯作者：
Neckers L
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：
4.8
作者：
Miller, Melissa;Shi, Jie;Zhu, Michael X.
通讯作者：
Zhu, Michael X.
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