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

Area of Science:

• Dermatology
• Molecular Biology
• Oncology

Background:

• Retinoic acid (RA) protects skin from UV damage and carcinomas, but its mechanism is unclear.
• UV irradiation poses risks including photoaging and skin cancer.
• Angiogenesis plays a role in skin damage and melanoma development.

Purpose of the Study:

• To elucidate the mechanism of retinoic acid's photoprotective effects.
• To investigate the role of seryl tRNA synthetase (SerRS) in UV-induced skin damage.
• To evaluate the therapeutic potential of combining all-trans retinoic acid (tRA) with an ATM inhibitor.

Main Methods:

• Investigated tRA's effect on SerRS expression in HaCaT and B16F10 cell lines.
• Utilized UV irradiation and ATM inhibitor (KU-55933) in cell culture and mouse models.
• Assessed VEGFA expression, skin photo damage, tumor angiogenesis, and melanoma growth in vivo.

Main Results:

• tRA directly induces SerRS transcription, acting as an anti-angiogenic factor.
• UV-activated ATM kinase phosphorylates SerRS, inhibiting its anti-angiogenic function by affecting VEGFA.
• Combination of tRA and an ATM inhibitor significantly enhanced anti-angiogenic effects, reduced skin damage, and inhibited melanoma growth.

Conclusions:

• tRA's protective mechanism involves inducing SerRS, an anti-angiogenic factor.
• UV-induced ATM activation counteracts tRA's effect by inhibiting SerRS.
• Combining tRA with an ATM inhibitor offers a promising strategy for preventing UV-induced skin damage and melanoma.