AHR controls skin cancerization through metabolism of FICZ, a UVA-photosensitizer

• Project/Area Number: 18K16036
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Nagoya City University
• Principal Investigator: Nakamura Motoki 名古屋市立大学, 医薬学総合研究院(医学), 講師 (70645051)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 芳香族炭化水素受容体 / 紫外線 / UVB / UVA / アポトーシス / 皮膚癌 / FICZ / 光発癌

Outline of Final Research Achievements

We observed activation of AHR and upregulation of CYP1A1 by FICZ, as well as induction of apoptosis by UVA-toxicity of FICZ itself. It was revealed that inhibition of AHR decreased CYP1A1 which metabolizes FICZ and increased apoptosis. It was proved that UVA-toxicity can be controlled by increasing / decreasing FICZ metabolism by AHR activity. UVA-toxicity of FICZ was also suppressed by CYP1A1 produced through AHR by UVB irradiation, and it was found that AHR inhibition increases UVA-induced apoptosis after UVB irradiation. Increased apoptosis leads to suppression of skin cancer. This is the innate mechanism of skin cancer suppression in our skin.

Academic Significance and Societal Importance of the Research Achievements

AHRによるFICZ/UVA毒性の制御と皮膚癌の発生の関連の証明は、紫外線発癌および職業性の発癌として知られるタールやアゾ色素、ヒ素の暴露による皮膚癌発症のメカニズムの解明につながる。また様々な疾患や皮膚老化の原因としてクローズアップされることの多いAHRの皮膚における重要な役割の発見であり、実用化の始まっているAHR阻害薬の外用薬等の汎用に警鐘を鳴らす。