α-MSH stimulation contributes to TGF-β1 production via MC1R-MITF signaling pathway in melanoma cell

Abstract

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that play critical roles in melanoma progression. Although the impact of TGF-β signaling on melanoma progression has been well characterized, little is known about the molecular mechanisms that control TGF-β production in melanoma cells. In this study, we describe a novel role for Melanocortin Receptor 1 (MC1R) in the regulation of TGF-β production. MC1R is a cell surface endocytic receptor expressed in melanoma cells and serves as a receptor for α-Melanocyte Stimulating Hormone (α-MSH). The activation of MC1R with α-MSH resulted in increased levels of TGF-β, which was mediated by ERK1/2 and p38 signaling pathways. Furthermore, Microphthalmia Transcription Factor (MITF), the master regulator of melanocytes, was found to act downstream of MC1R to regulate TGF-β production. Targeting of MC1R-MITF axis was effective to decrease TGF-β production, and resulted in delayed tumor growth of B16 melanoma in vivo. Collectively, these results give new insight into the molecular mechanisms that control TGF-β production in melanoma cells.