Discovery of FLF-15 as a novel selective inhibitor of ADAM17 to prevent hepatocellular carcinoma metastasis

Abstract

The poor prognosis of hepatocellular carcinoma (HCC) is mainly due to its high metastatic properties. Hence, metastasis inhibition might provide a reliable strategy for HCC treatment. As its pivotal role in the tumor cell proliferation, survival and metastasis, a disintegrin and metalloproteinase 17 (ADAM17) has become an attractive target for cancer therapy. Nevertheless, the role of ADAM17 in HCC metastasis and its underlying mechanisms remain enigmatic. In the present study, we discovered a novel ADAM17 inhibitor FLF-15, with an IC₅₀ value of 10.43 nM. Further mechanistic studies showed that FLF-15 inhibits HCC migration and invasion in vitro and in vivo mainly by reducing interleukin-6 receptor (IL-6R) shedding, which inhibits IL-6 trans-signaling, while also leading to a reduction in IL-6 levels and downregulation of IL-6 classic-signaling. Furthermore, we revealed an overlapping but distinct biological effects of IL-6 classic and trans-signaling in HCC. Specifically, JAK2/STAT3 and ERK1/2 signaling can be stimulated by both IL-6 classic and trans-signaling pathway. However, AKT appears to be only activated by IL-6 trans-signaling pathway, suggesting its essential role for FLF-15 induced metastasis suppression in HCC. Taken together, our study identified FLF-15 as a novel ADAM17 inhibitor and elucidated its underlying mechanism of HCC metastasis suppression. These findings indicated FLF-15 might be a promising candidate for the development of HCC therapeutic agents.

Keywords: ADAM17; Hepatocellular carcinoma; IL-6R; Migration and invasion; Selective inhibitor.