Garlic-derived compound S-allylmercaptocysteine inhibits hepatocarcinogenesis through targeting LRP6/Wnt pathway

Whether and how garlic-derived S -allylmercaptocysteine (SAMC) inhibits hepatocellular carcinoma ( HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor (LDLR)-related protein 6 ( LRP6) in HCCprogression and the anti- HCCmechanism of SAMC was examined in clinical sample, cell model and xenograft/orthotopic mouse models. We demonstrated that SAMC inhibited cell proliferation and tumorigenesis, while induced apoptosis of human HCCcells without influencing normal hepatocytes. SAMC directly interacted with Wnt-pathway co-receptor LRP6on the cell membrane. LRP6was frequently over-expressed in the tumor tissue of human HCCpatients (66.7% of 48 patients) and its over-expression only correlated with the over-expression of β -catenin, but not with age, gender, tumor size, stage and metastasis. Deficiency or over-expression of LRP6in hepatoma cells could partly mimic or counteract the anti-tumor properties of SAMC, respectively. In vivo administration of SAMC significantly suppressed the growth of Huh-7 xenograft/orthotopic HCCtumor without causing undesirable side effects. In addition, stable down-regulation of LRP6in Huh-7 facilitated the anti- HCCeffects of SAMC. In conclusion, LRP6can be a potential therapeutic target of HCC. SAMC is a promising specific anti-tumor agent for treating HCCsubtypes with Wnt activation at the hepatoma cell surface.