Cargando…

Receptor Tyrosine Kinase EphA5 Is a Functional Molecular Target in Human Lung Cancer

Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence...

Descripción completa

Detalles Bibliográficos
Autores principales: Staquicini, Fernanda I., Qian, Ming D., Salameh, Ahmad, Dobroff, Andrey S., Edwards, Julianna K., Cimino, Daniel F., Moeller, Benjamin J., Kelly, Patrick, Nunez, Maria I., Tang, Ximing, Liu, Diane D., Lee, J. Jack, Hong, Waun Ki, Ferrara, Fortunato, Bradbury, Andrew R. M., Lobb, Roy R., Edelman, Martin J., Sidman, Richard L., Wistuba, Ignacio I., Arap, Wadih, Pasqualini, Renata
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367244/
https://www.ncbi.nlm.nih.gov/pubmed/25623065
http://dx.doi.org/10.1074/jbc.M114.630525
_version_ 1782362508611289088
author Staquicini, Fernanda I.
Qian, Ming D.
Salameh, Ahmad
Dobroff, Andrey S.
Edwards, Julianna K.
Cimino, Daniel F.
Moeller, Benjamin J.
Kelly, Patrick
Nunez, Maria I.
Tang, Ximing
Liu, Diane D.
Lee, J. Jack
Hong, Waun Ki
Ferrara, Fortunato
Bradbury, Andrew R. M.
Lobb, Roy R.
Edelman, Martin J.
Sidman, Richard L.
Wistuba, Ignacio I.
Arap, Wadih
Pasqualini, Renata
author_facet Staquicini, Fernanda I.
Qian, Ming D.
Salameh, Ahmad
Dobroff, Andrey S.
Edwards, Julianna K.
Cimino, Daniel F.
Moeller, Benjamin J.
Kelly, Patrick
Nunez, Maria I.
Tang, Ximing
Liu, Diane D.
Lee, J. Jack
Hong, Waun Ki
Ferrara, Fortunato
Bradbury, Andrew R. M.
Lobb, Roy R.
Edelman, Martin J.
Sidman, Richard L.
Wistuba, Ignacio I.
Arap, Wadih
Pasqualini, Renata
author_sort Staquicini, Fernanda I.
collection PubMed
description Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G(1)/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. Finally, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lung cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications.
format Online
Article
Text
id pubmed-4367244
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher American Society for Biochemistry and Molecular Biology
record_format MEDLINE/PubMed
spelling pubmed-43672442015-03-27 Receptor Tyrosine Kinase EphA5 Is a Functional Molecular Target in Human Lung Cancer Staquicini, Fernanda I. Qian, Ming D. Salameh, Ahmad Dobroff, Andrey S. Edwards, Julianna K. Cimino, Daniel F. Moeller, Benjamin J. Kelly, Patrick Nunez, Maria I. Tang, Ximing Liu, Diane D. Lee, J. Jack Hong, Waun Ki Ferrara, Fortunato Bradbury, Andrew R. M. Lobb, Roy R. Edelman, Martin J. Sidman, Richard L. Wistuba, Ignacio I. Arap, Wadih Pasqualini, Renata J Biol Chem Cell Biology Lung cancer is often refractory to radiotherapy, but molecular mechanisms of tumor resistance remain poorly defined. Here we show that the receptor tyrosine kinase EphA5 is specifically overexpressed in lung cancer and is involved in regulating cellular responses to genotoxic insult. In the absence of EphA5, lung cancer cells displayed a defective G(1)/S cell cycle checkpoint, were unable to resolve DNA damage, and became radiosensitive. Upon irradiation, EphA5 was transported into the nucleus where it interacted with activated ATM (ataxia-telangiectasia mutated) at sites of DNA repair. Finally, we demonstrate that a new monoclonal antibody against human EphA5 sensitized lung cancer cells and human lung cancer xenografts to radiotherapy and significantly prolonged survival, thus suggesting the likelihood of translational applications. American Society for Biochemistry and Molecular Biology 2015-03-20 2015-01-26 /pmc/articles/PMC4367244/ /pubmed/25623065 http://dx.doi.org/10.1074/jbc.M114.630525 Text en © 2015 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/) applies to Author Choice Articles
spellingShingle Cell Biology
Staquicini, Fernanda I.
Qian, Ming D.
Salameh, Ahmad
Dobroff, Andrey S.
Edwards, Julianna K.
Cimino, Daniel F.
Moeller, Benjamin J.
Kelly, Patrick
Nunez, Maria I.
Tang, Ximing
Liu, Diane D.
Lee, J. Jack
Hong, Waun Ki
Ferrara, Fortunato
Bradbury, Andrew R. M.
Lobb, Roy R.
Edelman, Martin J.
Sidman, Richard L.
Wistuba, Ignacio I.
Arap, Wadih
Pasqualini, Renata
Receptor Tyrosine Kinase EphA5 Is a Functional Molecular Target in Human Lung Cancer
title Receptor Tyrosine Kinase EphA5 Is a Functional Molecular Target in Human Lung Cancer
title_full Receptor Tyrosine Kinase EphA5 Is a Functional Molecular Target in Human Lung Cancer
title_fullStr Receptor Tyrosine Kinase EphA5 Is a Functional Molecular Target in Human Lung Cancer
title_full_unstemmed Receptor Tyrosine Kinase EphA5 Is a Functional Molecular Target in Human Lung Cancer
title_short Receptor Tyrosine Kinase EphA5 Is a Functional Molecular Target in Human Lung Cancer
title_sort receptor tyrosine kinase epha5 is a functional molecular target in human lung cancer
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367244/
https://www.ncbi.nlm.nih.gov/pubmed/25623065
http://dx.doi.org/10.1074/jbc.M114.630525
work_keys_str_mv AT staquicinifernandai receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT qianmingd receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT salamehahmad receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT dobroffandreys receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT edwardsjuliannak receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT ciminodanielf receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT moellerbenjaminj receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT kellypatrick receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT nunezmariai receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT tangximing receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT liudianed receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT leejjack receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT hongwaunki receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT ferrarafortunato receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT bradburyandrewrm receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT lobbroyr receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT edelmanmartinj receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT sidmanrichardl receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT wistubaignacioi receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT arapwadih receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer
AT pasqualinirenata receptortyrosinekinaseepha5isafunctionalmoleculartargetinhumanlungcancer