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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., Budde, C., Böhm, A., Reinach, P.S., Dhandapani, P., Ljubojevic, N., Schweiger, M.W., von der Waydbrink, H., Reimers, I., 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 |
| ISSN: | 1663-9812 |
| Publisher: | Frontiers Media SA |
| Volume: | 9 |
| 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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