Activation of aryl hydrocarbon receptor-nuclear factor erythroid 2-related factor 2 axis by epidermal growth factor receptor inhibitors: a possible mechanism for acneiform eruption

Research Project

Project/Area Number	15H06477
Research Category	Grant-in-Aid for Research Activity Start-up
Allocation Type	Single-year Grants
Research Field	Dermatology
Research Institution	Kyushu University
Principal Investigator	Tsuji Gaku 九州大学, 大学病院, 講師 (20423551)
Project Period (FY)	2015-08-28 – 2017-03-31
Project Status	Completed (Fiscal Year 2016)
Budget Amount *help	¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000) Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords	芳香族炭化水素受容体 / 上皮成長因子受容体阻害薬 / 方向族炭化水素受容体
Outline of Final Research Achievements	Epidermal growth factor receptor inhibitors (EGFRIs) in the treatment for carcinomas cause acneiform eruption; however, its mechanism remains unknown. Because activation of aryl hydrocarbon receptor (AhR)-nuclear factor erythroid 2-related factor 2 (Nrf2) axis regulates keratinocyte differentiation and sebaceous gland activity, we hypothesized that activation of AhR-Nrf2 axis by EGFRIs might be involved in the development of acneiform eruption. We administrated gefitinib (GEF) to normal human epidermal keratinocytes (NHEKs) and SEB-1 cells, a human sebocyte cell line. GEF induced up-regulation of CYP1A1 expression in NHEKs and SEB-1 cells, which was enhanced by 6-formylindolo (3,2-b) carbazole (FICZ), an AhR ligand. GEF induced up-regulation of Nrf2 in NHEKs and production of sebeum in SEB-1 cells, which was enhanced by FICZ. Collectively, acceleration of AhR-Nrf2 axis and sebeceous lipogenesis by EGFRIs may be important during acneiform eruption.