title: Activation of mutated TRPA1 ion channel by resveratrol in human prostate cancer associated fibroblasts (CAF).
abstract: 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.
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Vancauwenberghe
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Noyer
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Derouiche
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Lemonnier
authors.affiliation: Faculté Libre de Médecine, Laboratoire d'Anatomie et de Cytologie Pathologique du groupement hospitalier de l'Institut Catholique de Lille, Lille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gosset
authors.affiliation: Cardiovascular and Respiratory Studies, The University of Hull, Castle Hill Hospital, Cottingham, United Kingdom.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Sadofsky
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Mariot
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Warnier
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bokhobza
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Slomianny
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Service d'Urologie de l'hôpital St-Philibert, Lille, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Mauroy
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Service d'Urologie de l'hôpital St-Philibert, Lille, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Bonnal
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Dewailly
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delcourt
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Allart
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Desruelles
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Natalia
authors.initials: N
authors.lastname: Prevarskaya
authors.affiliation: Univ. Lille, Inserm, U1003-PHYCEL-Physiologie Cellulaire, Equipe labellisée par la Ligue Nationale contre le cancer, Villeneuve d'Ascq, Lille, France.|Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
authors.forename: Morad
authors.identifier: 0000-0003-2744-0324
authors.initials: M
authors.lastname: Roudbaraki
mesh_terms: D000595:Amino Acid Sequence; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D000975:Antioxidants; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D013267:Stilbenes; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; D000077185:Resveratrol; D002118:Calcium
keywords: TRPA1; apoptosis; prostate cancer; resveratrol; tumor microenvironment