Pharmacological inhibition of Frizzled-7 displays anti-tumor properties in hepatocellular carcinoma.
OBJECTIVE
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.
INSERM, U871, 69003 Lyon.
Sarah Beseme
SB
Nambotin
Lydie
L
Lefrancois
Xavier
X
Sainsily
Pascale
P
Berthillon
Miran
M
Kim
Jack R
JR
Wands
Michele
M
Chevallier
Pierre
P
Jalinot
Jean-Yves
JY
Scoazec
Christian
C
Trepo
Fabien
F
Zoulim
Philippe
P
Merle
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000072261:Dishevelled Proteins; D051157:Frizzled Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000494:pharmacology*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000952:Antigens, Polyomavirus Transforming; D000970:Antineoplastic Agents; D000072261:Dishevelled Proteins; C115810:FZD7 protein, human; D051157:Frizzled Receptors; D010455:Peptides; D010750:Phosphoproteins; D043562:Receptors, G-Protein-Coupled; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta