期刊
MOLECULAR CARCINOGENESIS
卷 56, 期 8, 页码 1851-1867出版社
WILEY
DOI: 10.1002/mc.22642
关键词
apoptosis; prostate cancer; resveratrol; TRPA1; tumor microenvironment
资金
- Region Nord Pas-de-Calais, Institut National de la Sante et de la Recherche Medicale (INSERM)
- Ministere de l'Education Nationale de l'Enseignement Superieur et de la Recherche
- La Ligue Nationale Contre le Cancer
- Association pour la Recherche sur les Tumeurs de la Prostate (ARTP)
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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