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.
Highlights
Malignant melanoma is the most aggressive form of skin cancer
Icaritin (IT) is a flavonoid isolated from Herba Epimedii
We reported that IT exerted anti-melanoma activities, and these effects were partially due to inhibition of fatty acid synthase (FASN)/IGF-1 receptor (IGF-1R)/Signal transducer and activator of transcription 3 (STAT3) signaling
Summary
Malignant melanoma is the most aggressive form of skin cancer. It accounts for less than 2% of all skin cancer cases, it is responsible for 75 percent of deaths from skin cancers [1]. Targeted therapeutic agents (vemurafenib, trametinib, and imatinib, etc.) show promise in the survival rates in patients with advanced melanoma [4, 5]. The majority of patients who respond to the targeted therapies eventually develop resistance and disease progression [6]. Novel agents need to be developed for overcoming the limitations of the current therapeutic agents
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