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TRPM8 activation via 3-iodothyronamine blunts VEGF-induced transactivation of TRPV1 in human uveal melanoma cells

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Item Type:Article
Title:TRPM8 activation via 3-iodothyronamine blunts VEGF-induced transactivation of TRPV1 in human uveal melanoma cells
Creators Name:Walcher, L. and Budde, C. and Böhm, A. and Reinach, P.S. and Dhandapani, P. and Ljubojevic, N. and Schweiger, M.W. and von der Waydbrink, H. and Reimers, I. and Köhrle, J. and Mergler, S.
Abstract:In human uveal melanoma (UM), tumor enlargement is associated with increases in aqueous humor vascular endothelial growth factor-A (VEGF-A) content that induce neovascularization. 3-Iodothyronamine (3-T(1)AM), an endogenous thyroid hormone metabolite, activates TRP melastatin 8 (TRPM8), which blunts TRP vanilloid 1 (TRPV1) activation by capsaicin (CAP) in human corneal, conjunctival epithelial cells, and stromal cells. We compare here the effects of TRPM8 activation on VEGF-induced transactivation of TRPV1 in an UM cell line (92.1) with those in normal primary porcine melanocytes (PM) since TRPM8 is upregulated in melanoma. Fluorescence Ca(2+)-imaging and planar patch-clamping characterized functional channel activities. CAP (20 μM) induced Ca(2+) transients and increased whole-cell currents in both the UM cell line and PM whereas TRPM8 agonists, 100 μM menthol and 20 μM icilin, blunted such responses in the UM cells. VEGF (10 ng/ml) elicited Ca(2+) transients and augmented whole-cell currents, which were blocked by capsazepine (CPZ; 20 μM) but not by a highly selective TRPM8 blocker, AMTB (20 μM). The VEGF-induced current increases were not augmented by CAP. Both 3-T(1)AM (1 μM) and menthol (100 μM) increased the whole-cell currents, whereas 20 μM AMTB blocked them. 3-T1AM exposure suppressed both VEGF-induced Ca(2+) transients and increases in underlying whole-cell currents. Taken together, functional TRPM8 upregulation in UM 92.1 cells suggests that TRPM8 is a potential drug target for suppressing VEGF induced increases in neovascularization and UM tumor growth since TRPM8 activation blocked VEGF transactivation of TRPV1.
Keywords:Uveal Melanoma, 3-Iodothyronamine, Vascular Endothelial Growth Factor, Intracellular Ca(2+), Transient Receptor Potential Vanilloid 1 Channel, Transient Receptor Potential Melastatin 8
Source:Frontiers in Pharmacology
Publisher:Frontiers Media SA
Page Range:1234
Date:13 November 2018
Official Publication:https://doi.org/10.3389/fphar.2018.01234
PubMed:View item in PubMed

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