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-T1AM), 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 Ca2+-imaging and planar patch-clamping characterized functional channel activities. CAP (20 μM) induced Ca2+ 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 Ca2+ 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-T1AM (1 μM) and menthol (100 μM) increased the whole-cell currents, whereas 20 μM AMTB blocked them. 3-T1AM exposure suppressed both VEGF-induced Ca2+ 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.
Highlights
Among all cancers of the eye, uveal melanoma (UM) is the most frequent form in adults
We found that TRP melastatin 8 (TRPM8) is overexpressed in highly malignant retinoblastoma and uveal melanoma along with TRP vanilloid 1 (TRPV1) compared to their levels in healthy human uvea or retina (Mergler et al, 2012a, 2014)
We show here that crosstalk between members of this receptor triad affects Ca2+ signaling responses induced by Vascular endothelial growth factor receptor (VEGFR) transactivation of TRPV1 in UM 92.1 melanoma cells
Summary
Among all cancers of the eye, uveal melanoma (UM) is the most frequent form in adults. There is a pressing need for developing alternative approaches to treat this disease especially since there are no FDA approved drugs available for suppressing metastatic melanoma. A preclinical approach targeting angiogenesis in combination with irradiation has been reported using bevacizumab, a monoclonal antibody binding and inhibiting vascular endothelial growth factor (VEGF; Sudaka et al, 2013). As a matter of fact, such treatment is reported to even promote expansion of melanoma cells in vitro (Dithmer et al, 2017). Neoadjuvant intravitreous injection of this VEGF trap failed to shrink large size melanoma and is even counter indicated in these cases because it may instead even promote melanoma growth (Francis et al, 2017)
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