Targeting Angiogenesis by Blocking the ATM–SerRS–VEGFA Pathway for UV-Induced Skin Photodamage and Melanoma Growth

Abstract

Retinoic acid (RA) has been widely used to protect skin from photo damage and skin carcinomas caused by solar ultraviolet (UV) irradiation, yet the mechanism remains elusive. Here, we report that all-trans retinoic acid (tRA) can directly induce the expression of a newly identified potent anti-angiogenic factor, seryl tRNA synthetase (SerRS), whose angiostatic role can, however, be inhibited by UV-activated ataxia telangiectasia mutated (ATM) kinase. In both a human epidermal cell line, HaCaT, and a mouse melanoma B16F10 cell line, we found that tRA could activate SerRS transcription through binding with the SerRS promoter. However, UV irradiation induced activation of ATM-phosphorylated SerRS, leading to the inactivation of SerRS as a transcriptional repressor of vascular endothelial growth factor A (VEGFA), which dampened the effect of tRA. When combined with ATM inhibitor KU-55933, tRA showed a greatly enhanced efficiency in inhibiting VEGFA expression and a much better protection of mouse skin from photo damage. Also, we found the combination greatly inhibited tumor angiogenesis and growth in mouse melanoma xenograft in vivo. Taken together, tRA combined with an ATM inhibitor can greatly enhance the anti-angiogenic activity of SerRS under UV irradiation and could be a better strategy in protecting skin from angiogenesis-associated skin damage and melanoma caused by UV radiation.