Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity.
Targeting tyrosine kinase receptors (RTKs) with specific Abs is a promising therapeutic approach for cancer treatment, although the molecular mechanism(s) responsible for the Abs' biological activity are not completely known. We targeted the transmembrane RTK for hepatocyte growth factor (HGF) with a monoclonal Ab (DN30). In vitro, chronic treatment of carcinoma cell lines resulted in impairment of HGF-induced signal transduction, anchorage-independent growth, and invasiveness. In vivo, administration of DN30 inhibited growth and metastatic spread to the lung of neoplastic cells s.c. transplanted into immunodeficient nu/nu mice. This Ab efficiently down-regulates HGF receptor through a molecular mechanism involving a double proteolytic cleavage: (i) cleavage of the extracellular portion, resulting in "shedding" of the ectodomain, and (ii) cleavage of the intracellular domain, which is rapidly degraded by the proteasome. Interestingly, the "decoy effect" generated by the shed ectodomain, acting as a dominant negative molecule, enhanced the inhibitory effect of the Ab.
Petrelli
Annalisa
A
Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, 10060 Candiolo, Italy.
Circosta
Paola
P
Granziero
Luisa
L
Mazzone
Massimiliano
M
Pisacane
Alberto
A
Fenoglio
Silvia
S
Comoglio
Paolo M
PM
Giordano
Silvia
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D019859:Proto-Oncogene Proteins c-met