Modeling ErbB2-p130Cas interaction to design new potential anticancer agents

Scientific Reports
Andrea CostamagnaSara Cabodi

Abstract

The ErbB2 receptor tyrosine kinase is overexpressed in approximately 15-20% of breast tumors and associated with aggressive disease and poor clinical outcome. p130Cas represents a nodal scaffold protein regulating cell survival, migration and proliferation in normal and pathological contexts. p130Cas overexpression in ErbB2 human breast cancer correlates with poor prognosis and metastasis formation. Recent data indicate that p130Cas association to ErbB2 protects ErbB2 from degradation, thus enhancing tumorigenesis. Therefore, inhibiting p130Cas/ErbB2 interaction might represent a new therapeutic strategy to target breast cancer. Here we demonstrate by performing Molecular Modeling, Molecular Dynamics, dot blot, ELISA and fluorescence quenching experiments, that p130Cas binds directly to ErbB2. Then, by structure-based virtual screening, we identified two potential inhibitors of p130Cas/ErbB2 interaction. Their experimental validation was performed in vitro and in ErbB2-positive breast cancer cellular models. The results highlight that both compounds interfere with p130Cas/ErbB2 binding and significantly affect cell proliferation and sensitivity to Trastuzumab. Overall, this study identifies p130Cas/ErbB2 complex as a potential ...Continue Reading

References

Nov 7, 1995·Proceedings of the National Academy of Sciences of the United States of America·T R Polte, S K Hanks
Jan 1, 1997·Biopolymers·D C DalgarnoR J Rickles
Mar 24, 2005·Journal of Molecular Biology·Magdalena WisniewskaRichard A Engh
Feb 24, 2006·Nature Reviews. Molecular Cell Biology·Patrick Aloy, Robert B Russell
Apr 4, 2006·Trends in Cell Biology·Paola DefilippiSara Cabodi
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Jun 26, 2009·Current Opinion in Chemical Biology·Michelle R Arkin, Adrian Whitty
May 28, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sara CabodiPaola Defilippi
Jul 7, 2010·Cell·Mark A Lemmon, Joseph Schlessinger
Nov 26, 2010·Nature Reviews. Cancer·Sara CabodiPaola Defilippi
Dec 14, 2011·The New England Journal of Medicine·José BaselgaUNKNOWN CLEOPATRA Study Group
Jun 20, 2012·FEBS Letters·Kalle Saksela, Perttu Permi
Sep 14, 2012·Journal of Chemical Information and Modeling·Simon CrossGabriele Cruciani
Oct 2, 2012·The New England Journal of Medicine·Sunil VermaUNKNOWN EMILIA Study Group
Apr 12, 2014·Current Opinion in Structural Biology·Andras Szilagyi, Yang Zhang
Sep 16, 2014·International Journal of Cancer. Journal International Du Cancer·Jacques FerlayFreddie Bray
Jan 22, 2015·Breast Cancer Research : BCR·Giusy TornilloSara Cabodi
Apr 11, 2015·Journal of Medicinal Chemistry·Douglas E V PiresDavid B Ascher
Apr 16, 2015·BioMed Research International·Nalo HamiltonRichard Pietras
Nov 18, 2015·Journal of Chemical Theory and Computation·James A MaierCarlos Simmerling
Nov 29, 2015·Seminars in Oncology·Elisa ZanardiSerena Di Cosimo
Nov 29, 2015·Nucleic Acids Research·Holger DinkelToby J Gibson
Dec 5, 2015·Frontiers in Pharmacology·Aline Appert-CollinAmar Bennasroune
Mar 5, 2016·Cell Communication and Signaling : CCS·Carles Corbi-Verge, Philip M Kim
May 21, 2017·The Lancet Oncology·Filippo Montemurro

❮ Previous
Next ❯

Methods Mentioned

BETA
affinity purification
dot blot
immunoprecipitation
fluorescence assay
co-immunoprecipitation
transfection
ELISA
Fluorescence
PCR

Software Mentioned

FLAP
Eukaryotic Linear Motif ( ELM )
MOE Protonate3D
Glob
MOE
Antechamber
pkCSM
BiKi Life Science
ClogP
GraphPad Prism7

Related Concepts

Related Feeds

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.