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

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 - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States of America.

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 ┬Čover 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.

No MeSH data available.


Related in: MedlinePlus

Sensitivity to englerin A induced growth inhibition correlates with expression of TRPC4.(A) Volcano plot of gene expression features. X- axis indicates fold change of feature in sensitive versus refractory cell lines and Y-axis indicates statistical significance. (B) Waterfall plot showing TRPC4 expression levels (affymetrix microarray units) in englerin A sensitive (red) and refractory (blue) tumor cell lines.
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pone.0127498.g003: Sensitivity to englerin A induced growth inhibition correlates with expression of TRPC4.(A) Volcano plot of gene expression features. X- axis indicates fold change of feature in sensitive versus refractory cell lines and Y-axis indicates statistical significance. (B) Waterfall plot showing TRPC4 expression levels (affymetrix microarray units) in englerin A sensitive (red) and refractory (blue) tumor cell lines.

Mentions: Cellular features of the englerin A-sensitive cell lines, including known mutations, gene expression levels, gene copy number and pathway activation were compared to features of lineage matched groups of englerin A resistant cell lines. The volcano plot of gene expression features (Fig 3A) shows that four Affymetrix probe sets stand out as most significantly associated with englerin A sensitivity. These probes all belong to the same gene, TRPC4. A waterfall plot of TRPC4 expression in englerin A sensitive and refractory cell lines indicates that the majority of sensitive cell lines have higher levels of TRPC4 mRNA expression than do the refractory cell lines (Fig 3B). Taken together, the data above shows that TRPC4 expression is the feature that best correlates with englerin A sensitivity and suggested the simple hypothesis that TRPC4 is the efficacy target for englerin A.


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

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 - PLoS ONE (2015)

Sensitivity to englerin A induced growth inhibition correlates with expression of TRPC4.(A) Volcano plot of gene expression features. X- axis indicates fold change of feature in sensitive versus refractory cell lines and Y-axis indicates statistical significance. (B) Waterfall plot showing TRPC4 expression levels (affymetrix microarray units) in englerin A sensitive (red) and refractory (blue) tumor cell lines.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4476799&req=5

pone.0127498.g003: Sensitivity to englerin A induced growth inhibition correlates with expression of TRPC4.(A) Volcano plot of gene expression features. X- axis indicates fold change of feature in sensitive versus refractory cell lines and Y-axis indicates statistical significance. (B) Waterfall plot showing TRPC4 expression levels (affymetrix microarray units) in englerin A sensitive (red) and refractory (blue) tumor cell lines.
Mentions: Cellular features of the englerin A-sensitive cell lines, including known mutations, gene expression levels, gene copy number and pathway activation were compared to features of lineage matched groups of englerin A resistant cell lines. The volcano plot of gene expression features (Fig 3A) shows that four Affymetrix probe sets stand out as most significantly associated with englerin A sensitivity. These probes all belong to the same gene, TRPC4. A waterfall plot of TRPC4 expression in englerin A sensitive and refractory cell lines indicates that the majority of sensitive cell lines have higher levels of TRPC4 mRNA expression than do the refractory cell lines (Fig 3B). Taken together, the data above shows that TRPC4 expression is the feature that best correlates with englerin A sensitivity and suggested the simple hypothesis that TRPC4 is the efficacy target for englerin A.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States of America.

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 ┬Čover 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.

No MeSH data available.


Related in: MedlinePlus