Icaritin, a novel FASN inhibitor, exerts anti-melanoma activities through IGF-1R/STAT3 signaling

// Jinfeng Wu 1, 2 , Juan Du 1 , Xiuqiong Fu 1 , Bin Liu 1, 3 , Huihui Cao 1 , Ting Li 1 , Tao Su 1 , Jinhua Xu 2 , Anfernee Kai-Wing Tse 1 , Zhi-Ling Yu 1, 4 1 Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong 2 Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China 3 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China 4 Institute of Integrated Bioinfomedicine and Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China Correspondence to: Anfernee Kai-Wing Tse, email: anfernee@hkbu.edu.hk Zhi-Ling Yu, email: zlyu@hkbu.edu.hk Keywords: icaritin, melanoma, STAT3, IGF-1R, FASN Received: October 09, 2015      Accepted: May 25, 2016      Published: June 13, 2016 ABSTRACT Icaritin (IT) is a flavonoid isolated from Herba Epimedii . In this study, we evaluated the anti-melanoma activities of IT, and determined its cytotoxic mechanism. We found that IT exerted cytotoxicity to melanoma cells. Furthermore, IT induced melanoma cell apoptosis, which was accompanied with PARP cleavage. Mechanistically, IT suppressed p-STAT3 (tyr705) level in parallel with increases of p-STAT3 (ser727), p-ERK and p-AKT. IT significantly inhibited STAT3 nuclear translocation and reduced the levels of STAT3 -targeted genes. IT also inhibited IGF-1-induced STAT3 activation through down-regulation of total IGF-1R level. No dramatic changes in IGF-1R mRNA levels were observed in IT-treated cells, suggesting that IT acted primarily at a post-transcriptional level. Using molecular docking analysis, IT was identified as a novel fatty acid synthase (FASN) inhibitor. We found that IT reduced the level of total IGF-1R via FASN inhibition. In summary, we reported that IT exerted anti-melanoma activities, and these effects were partially due to inhibition of FASN/IGF-1R/STAT3 signaling.