Iciartin, a novel FASN inhibitor, exerts anti-melanoma activities through IGF-1R/STAT3 signaling.
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.
Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.|Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
Jinfeng
J
Wu
Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
Juan
J
Du
Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
Xiuqiong
X
Fu
Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.|School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
Bin
B
Liu
Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
Huihui
H
Cao
Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
Ting
T
Li
Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
Tao
T
Su
Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
Jinhua
J
Xu
Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
Anfernee Kai-Wing
AK
Tse
Center for Cancer and Inflammation Research, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.|Institute of Integrated Bioinfomedicine and Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China.
Zhi-Ling
ZL
Yu
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D062105:Molecular Docking Simulation; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D017526:Receptor, IGF Type 1; C499403:icaritin
FASN; IGF-1R; STAT3; icartin; melanoma