Abstract |
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.
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Authors | Annalisa Petrelli, Paola Circosta, Luisa Granziero, Massimiliano Mazzone, Alberto Pisacane, Silvia Fenoglio, Paolo M Comoglio, Silvia Giordano |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 103
Issue 13
Pg. 5090-5
(Mar 28 2006)
ISSN: 0027-8424 [Print] United States |
PMID | 16547140
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal
- Proto-Oncogene Proteins c-met
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Topics |
- Animals
- Antibodies, Monoclonal
(immunology, pharmacology)
- Cell Line, Tumor
- Cell Proliferation
- Cell Transformation, Neoplastic
(immunology, pathology)
- Disease Progression
- Down-Regulation
(drug effects)
- Female
- Humans
- Mice
- Neoplasms
(immunology, metabolism)
- Phenotype
- Protein Processing, Post-Translational
(drug effects)
- Proto-Oncogene Proteins c-met
(chemistry, metabolism)
- Signal Transduction
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