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Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation.

Carson, Cheryl and Raman, Pichai and Tullai, Jennifer and Xu, Lei and Henault, Martin and Thomas, Emily and Yeola, Sarita and Lao, Jianmin and McPate, Mark and Verkuyl, J Martin and Marsh, George and Sarber, Jason and Amaral, Adam and Bailey, Scott and Lubicka, Danuta and Pham, Helen and Miranda, Nicolette and Ding, Jian and Tang, Hai-Ming and Ju, Haisong and Tranter, Pamela and Ji, Nan and Krastel, Philipp and Jain, Rishi K and Schumacher, Andrew M and Loureiro, Joseph J and George, Elizabeth and Berellini, Giuliano and Ross, Nathan T and Bushell, Simon M and Erdemli, Gül and Solomon, Jonathan M (2015) Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation. PloS one, 10 (6). e0127498. ISSN 1932-6203

Abstract

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.

Item Type: Article
Date Deposited: 11 Jul 2016 23:45
Last Modified: 11 Jul 2016 23:45
URI: https://oak.novartis.com/id/eprint/29748

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