Pharmacological inhibition of Frizzled-7 displays anti-tumor properties in hepatocellular carcinoma.

ABSTRACT

BACKGROUND & AIMS: We previously reported the frequent overexpression of the FZD7 membrane receptor in hepatocellular carcinoma (HCC) and its role for controlling cancer phenotype. Herein, this study aimed at assessing the anticancer properties of compounds inhibiting FZD7 activity by disrupting its binding with the cytosolic Dishevelled (DVL) adaptator. METHODS: We have designed small interfering peptides (RHPDs) that are able to enter within cells and to competitively antagonize the binding of FZD7 to the PDZ domain of DVL. Their anti-neoplastic properties were assessed in vitro on a panel of human HCC cell lines and in vivo on the SV40-TAg transgenic mouse model of HCC. RESULTS: We have shown that RHPDs decrease cell viability via apoptosis depending on their affinity for PDZ, with a therapeutic index between cancerous and non-cancerous cells. RHPD properties were linked to ß-catenin degradation and PKCδ activation. In transgenic mice, intra-tumor injection of RHPDs inhibited HCC progression. CONCLUSIONS: We have completed a proof-of-concept showing that in vitro and in vivo the pharmacological inhibition of FZD7 displays anti-cancerous properties against HCC. The mechanisms can involve ß-catenin and PKCδ modulations. Further studies are warranted to design protocols showing the compatibility with systemic in vivo applications.