Melanocyte UV resistance: Feelin' the endothelin

Abstract

UV radiation is among the most important environmental carcinogens, abundant in sunshine and artificial tanning devices. UV is also among the most important causative factors for the development of melanoma, the most lethal of all UV-induced skin malignancies. Roughly 75 000 people in the United States alone are diagnosed with melanoma and nearly 10 000 die of the disease annually. UV mutations clearly contribute to the development of melanoma (1). In fact, the mutational burden of melanoma is among the very highest of all malignancies with an overrepresentation of UV signature mutations (2). Despite aggressive educational efforts to warn the public about the dangers of purposeful exposure to UV, recreational tanning is widespread and increasing in popularity. Although tremendous advances -most notably in immunotherapies and molecular targeting of the MAP kinase cascade -are being made in the treatment of advanced melanoma, the prognosis for the vast majority of patients with advanced disease remains dismal. The recent contribution by the Abdel-Malek group (3) is important because it informs us of how melanocytes cope with UV radiation and introduces a novel and potentially exploitable pathway for the prevention of melanoma. On the surface, it seems counter-intuitive that the efficiency whereby melanocytes resist or repair UV damage would not be in a continuous 'optimal' state of UV-readiness given their positioning in the skin. However, what has emerged through this report and others is that melanocytic UV resistance is regulated by paracrine factors, most notably, the MSH-MC1R-cAMP signalling cascade (4,5). The Abdel-Malek group now adds endothelin-1 (ET1) and endothelin B receptor (ETBR) signalling as a distinct means by which melanocytes protect themselves against UV damage.Using primary human melanocytes, von Koschembahr (3) and colleagues found that pretreating melanocytes with ET1 prior to UV exposure decreased levels of photodimers in melanocytes. Protection by ET1 was observed even immediately after UV exposure, suggesting that ET1 may somehow 'prime' melanocytes from accumulating UV photodamage, even before repair can occur. However, the beneficial effects of ET1 were observed as long as 48 h after UV, raising the possibility that ETBR signalling may enhance the nucleotide excision repair (NER) pathway in some way. Importantly, ET1 treatment did not raise cAMP levels; therefore the ET1-ETBR signalling pathway does not simply rescue MC1R signals, and ET1 had no effect on the proliferation of melanocytes in the absence of cAMP-inducing factors. Melanin production was similarly unaffected in the time course presented, suggesting that reductions in UV burden are not simply explained by the UV-blocking effect by pigment. ET1 pretreatment decreased UV damage (as measured by cyclopyrimidine dimer load) by as much as 40% after UV damage and decreased UV-mediated apoptosis by even larger margins. Clearly, ET1 augments melanocytic resistance to UV injury.ET1 treatment activated both JNK and p38 signalling as det...

Gnaq and Gna11 in the Endothelin Signaling Pathway and Melanoma

“…Larger studies and other populations are necessary to validate these findings. Endothelin signaling has also been suggested to enhance nucleotide excision repair following UV damage, and so a deficiency in this process could possibly act synergistically with a weak checkpoint ( D’Orazio, 2015 ; von Koschembahr et al, 2015 ).…”