Androgens regulate broad physiologic and pathologic processes, including external genitalia development, prostate cancer progression, and anti-inflammatory effects in both cancer and asthma. In prostate cancer, several lines of evidence have implicated dietary and endogenous fatty acids in cell invasion, angiogenesis, and treatment resistance. However, the role of fatty acids in steroidogenesis and the mechanisms by which alterations in this pathway occur are not well understood. Here, we show that, of a panel of fatty acids tested, arachidonic acid and its specific metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) regulate androgen metabolism. Arachidonic acid is metabolized to 5-HETE and reduces androgens by inducing AKR1C2 and AKR1C3 expression in human prostate, breast, and lung epithelial cells. Finally, we provide evidence that these effects require the expression of the antioxidant response sensor, nuclear factor erythroid 2-related factor 2 (Nrf2). Our findings identify an interconnection between conventional fatty acid metabolism and steroid metabolism that has broad relevance to androgen physiology and inflammatory regulation.
Endocrinology. 2022 Nov 22 [Epub ahead of print]
Aimalie L Hardaway, Maryam Goudarzi, Michael Berk, Yoon-Mi Chung, Renliang Zhang, Jianneng Li, Eric Klein, Nima Sharifi
Genitourinary Malignancies Research Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Proteomics and Metabolomics Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH., Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio.