TRPA1 channels as targets for resveratrol and related stilbenoids

Nalli, Marianna; Ortar, Giorgio; Moriello, Aniello Schiano; Morera, Enrico; Marzo, Vincenzo Di; Petrocellis, Luciano De

doi:10.1016/j.bmcl.2015.12.065

Cited by 16 publications

(17 citation statements)

References 44 publications

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“…Concerning the modulation of TRPA1 activity by RES, it has been shown that the mouse and rat ortholog of TRPA1 channels are inhibited by the polyphenol . In the present work, we show that RES also inhibits the wild type (WT) human TRPA1 (Fig.…”

Section: Discussionsupporting

confidence: 63%

“…5E,F) Concerning the modulation of TRPA1 activity by RES, it has been shown that the mouse and rat ortholog of TRPA1 channels are inhibited by the polyphenol. 21,22 In the present work, we show that RES also inhibits the wild type (WT) human TRPA1 (Fig. 3F) In the present study, in order to better understand the discrepancy between wt-hTRPA1 (inhibited by RES) and the PCa CAF-expressed TRPA1 (activated by RES), we cloned and sequenced the entire cDNA sequence of the TRPA1 channel expressed in human PCa CAF cells.…”

Section: Resveratrol Activates Mutated Trpa1 In Caf Cellsmentioning

confidence: 52%

“…These observations are surprising because RES is known to inhibit mouse and rat TRPA1 channel . Using calcium imaging experiments, we, therefore, studied the effects of the TRPA1 activator Allylisothiocyanate (AITC, 30 μM) on intracellular calcium concentration in the presence or absence of RES (25 μM) in HEK293 cells transiently transfected with human wild type TRPA1 (wt‐TRPA1) expression vector (HEK‐wtTRPA1).…”

Section: Resultsmentioning

confidence: 99%

“…Protein sequences alignment (Fig. A) showed 1 mutation (K539R) and 2 SNPs (Y69C and K186N) (according to http://exac.broadinstitute.org/gene/ENSG00000104321) in TRPA1 N‐terminal domain known to be involved in TRPA1 activity properties, while the C‐terminal domain amino acids sequences presented 100% identity with wt‐hTRPA1 (Fig. B).…”

Section: Resultsmentioning

confidence: 99%

“…These observations are surprising because RES is known to inhibit mouse and rat TRPA1 channel. 21,22 Using calcium imaging experiments, we, therefore, studied the effects of the TRPA1 activator (Fig. 4F,G).…”

Section: Among the Inhibitors Tested Only Trpa1 Inhibitors (Hc-030031mentioning

confidence: 99%

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Activation of mutated TRPA1 ion channel by resveratrol in human prostate cancer associated fibroblasts (CAF)

Vancauwenberghe

Noyer

Derouiche

et al. 2017

Molecular Carcinogenesis

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Previous studies showed the effects of resveratrol (RES) on several cancer cells, including prostate cancer (PCa) cell apoptosis without taking into consideration the impact of the tumor microenvironment (TME). The TME is composed of cancer cells, endothelial cells, blood cells, and cancer-associated fibroblasts (CAF), the main source of growth factors. The latter cells might modify in the TME the impact of RES on tumor cells via secreted factors. Recent data clearly show the impact of CAF on cancer cells apoptosis resistance via secreted factors. However, the effects of RES on PCa CAF have not been studied so far. We have investigated here for the first time the effects of RES on the physiology of PCa CAF in the context of TME. Using a prostate cancer CAF cell line and primary cultures of CAF from prostate cancers, we show that RES activates the N-terminal mutated Transient Receptor Potential Ankyrin 1 (TRPA1) channel leading to an increase in intracellular calcium concentration and the expression and secretion of growth factors (HGF and VEGF) without inducing apoptosis in these cells. Interestingly, in the present work, we also show that when the prostate cancer cells were co-cultured with CAF, the RES-induced cancer cell apoptosis was reduced by 40%, an apoptosis reduction canceled in the presence of the TRPA1 channel inhibitors. The present work highlights CAF TRPA1 ion channels as a target for RES and the importance of the channel in the epithelial-stromal crosstalk in the TME leading to resistance to the RES-induced apoptosis.

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Section: Discussionsupporting

confidence: 63%

Section: Resveratrol Activates Mutated Trpa1 In Caf Cellsmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Among the Inhibitors Tested Only Trpa1 Inhibitors (Hc-030031mentioning

confidence: 99%

See 3 more Smart Citations

Activation of mutated TRPA1 ion channel by resveratrol in human prostate cancer associated fibroblasts (CAF)

Vancauwenberghe

Noyer

Derouiche

et al. 2017

Molecular Carcinogenesis

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Insights into Molecular Interactions and Biological Effect of Natural Stilbenoids at the TRPA1 Ion Channel

Saadabadi,

Rantanen,

Marimuthu

et al. 2024

ChemMedChem

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Natural stilbenoids, polyphenolic compounds notably found in Scots pine and Norway spruce, have been shown to exhibit analgesic and anti‐inflammatory effects through the TRPA1 channel, making them promising hits for the development of novel agents to treat inflammatory diseases and pain. In this study, we computationally investigated the putative binding sites of natural stilbenoids at the TRPA1 channel. Specifically, we employed molecular docking and MD simulation approaches to explore three known ligand binding sites at TRPA1. Furthermore, the biological effect of the studied compounds on TRPA1 was assessed in vitro using a fluorescent imaging plate reader (FLIPR™) calcium assay. Our modeling results suggest the stilbenoids exhibit higher affinity to the two agonist binding sites than the antagonistic site. Consistent with this, the in vitro results showed that the stilbenoids act as moderate TRPA1 channel agonists and likely inhibit the channel through a desensitization mechanism rather than act as pure TRPA1 antagonists. Additionally, our bias‐force pulling simulations proposed an additional binding pocket for the natural stilbenoids that is distinct from the known ligand binding sites at TRPA1. The results of the study give useful insights into structure‐based design and development of novel therapeutic TRPA1 modulators.

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Synthesis of resveratrol derivatives as new analgesic drugs through desensitization of the TRPA1 receptor

Nakao

Mabuchi

Wang

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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TRPA1 channels as targets for resveratrol and related stilbenoids

Cited by 16 publications

References 44 publications

Activation of mutated TRPA1 ion channel by resveratrol in human prostate cancer associated fibroblasts (CAF)

Activation of mutated TRPA1 ion channel by resveratrol in human prostate cancer associated fibroblasts (CAF)

Insights into Molecular Interactions and Biological Effect of Natural Stilbenoids at the TRPA1 Ion Channel

Synthesis of resveratrol derivatives as new analgesic drugs through desensitization of the TRPA1 receptor

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