Abstract
Simple SummarySixteen G-protein-coupled receptors (GPCRs) have been involved in melanogenesis or melanomagenesis. Here, we review these GPCRs, their associated signaling, and therapies.G-protein-coupled receptors (GPCRs) serve prominent roles in melanocyte lineage physiology, with an impact at all stages of development, as well as on mature melanocyte functions. GPCR ligands are present in the skin and regulate melanocyte homeostasis, including pigmentation. The role of GPCRs in the regulation of pigmentation and, consequently, protection against external aggression, such as ultraviolet radiation, has long been established. However, evidence of new functions of GPCRs directly in melanomagenesis has been highlighted in recent years. GPCRs are coupled, through their intracellular domains, to heterotrimeric G-proteins, which induce cellular signaling through various pathways. Such signaling modulates numerous essential cellular processes that occur during melanomagenesis, including proliferation and migration. GPCR-associated signaling in melanoma can be activated by the binding of paracrine factors to their receptors or directly by activating mutations. In this review, we present melanoma-associated alterations of GPCRs and their downstream signaling and discuss the various preclinical models used to evaluate new therapeutic approaches against GPCR activity in melanoma. Recent striking advances in our understanding of the structure, function, and regulation of GPCRs will undoubtedly broaden melanoma treatment options in the future.
Highlights
G-protein-coupled receptors (GPCRs) participate in intercellular communication by receiving extracellular stimuli from the microenvironment
The GPCR family is composed of receptors that share a common structure, consisting of seven transmembrane helices that are associated with a heterotrimeric G-protein
97,000 deaths estimated for 2040, despite the development of new therapies in the second half of the 2010s [4]. These treatments are based on two approaches: (1) inhibition of the MAPK/ERK pathway in melanoma using a combination of activated BRAF and MEK inhibitors—targeted therapy (TT)—and (2) inhibition of immune cell exhaustion using the checkpoint inhibitors iCTL4 and iPD1—immunotherapy (IT)—[5]
Summary
G-protein-coupled receptors (GPCRs) participate in intercellular communication by receiving extracellular stimuli from the microenvironment. The GPCR family is composed of receptors that share a common structure, consisting of seven transmembrane helices that are associated with a heterotrimeric G-protein These receptors are known to regulate many essential physiological processes and their aberrant expression or activity can contribute to human diseases, including cancer. 97,000 deaths estimated for 2040, despite the development of new therapies in the second half of the 2010s [4] These treatments are based on two approaches: (1) inhibition of the MAPK/ERK pathway in melanoma using a combination of activated BRAF and MEK inhibitors—targeted therapy (TT)—and (2) inhibition of immune cell exhaustion using the checkpoint inhibitors iCTL4 and iPD1—immunotherapy (IT)—[5].
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