@article{bd4538d30f21420fbc5fb6c06fd77bf9,
title = "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 β-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 β-catenin and PKCδ modulations. Further studies are warranted to design protocols showing the compatibility with systemic in vivo applications.",
keywords = "Dishevelled, Frizzled, Hepatocellular carcinoma, Targeted therapy",
author = "Nambotin, {Sarah Beseme} and Lydie Lefrancois and Xavier Sainsily and Pascale Berthillon and Miran Kim and Wands, {Jack R.} and Michele Chevallier and Pierre Jalinot and Scoazec, {Jean Yves} and Christian Trepo and Fabien Zoulim and Philippe Merle",
note = "Funding Information: We thank the French National Biological Resources Centre for providing us with the frozen human liver tissues which were obtained following approved consent from the French Liver Tumor Network Scientific Committee. The French Liver Tumor Network is funded by the Institut National de la Sant{\'e} Et de la Recherche M{\'e}dicale (INSERM) and the Agence Nationale de la Recherche (ANR) . We thank the Centre d{\textquoteright}Etude et de Recherche Multimodal Et Pluridisciplinaire en Imagerie du vivant (CERMEP) for ultrasound examination of mouse liver, and Naoaki Fujii (Department of Chemical Biology and Therapeutics, St. Jude Children{\textquoteright}s Research Hospital, Memphis, TN 38105, USA) for his kind gift of the FJ9 drug. We thank the Canceropole Lyon Auvergne Rhone Alpes (CLARA) for supporting the platform of isolation and purification of human primary hepatocytes. Funding Information: This work was supported by French grants from CLARA, ARC (#3676), EZUS Lyon, (company of Claude Bernard Lyon-1 University, financial support awarded by OSEO “Innovation for Research Companie”), an unrestricted grant from the Association Fran{\c c}aise de l{\textquoteright}Etude du Foie (AFEF) and an interface contract with INSERM for P. Merle. ",
year = "2011",
month = feb,
day = "1",
doi = "10.1016/j.jhep.2010.06.033",
language = "English",
volume = "54",
pages = "288--299",
journal = "Journal of Hepatology",
issn = "0168-8278",
number = "2",
}