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c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression

Despite 35 years of clinical trials, there is little improvement in one-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates...

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Autores principales: Ganguly, Sourik S., Fiore, Leann S., Sims, Jonathan T., Friend, J. Woodrow, Srinivasan, Divyamani, Thacker, Matthew A., Cibull, Michael L., Wang, Chi, Novak, Marian, Kaetzel, David M., Plattner, Rina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235241/
https://www.ncbi.nlm.nih.gov/pubmed/21892207
http://dx.doi.org/10.1038/onc.2011.361
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author Ganguly, Sourik S.
Fiore, Leann S.
Sims, Jonathan T.
Friend, J. Woodrow
Srinivasan, Divyamani
Thacker, Matthew A.
Cibull, Michael L.
Wang, Chi
Novak, Marian
Kaetzel, David M.
Plattner, Rina
author_facet Ganguly, Sourik S.
Fiore, Leann S.
Sims, Jonathan T.
Friend, J. Woodrow
Srinivasan, Divyamani
Thacker, Matthew A.
Cibull, Michael L.
Wang, Chi
Novak, Marian
Kaetzel, David M.
Plattner, Rina
author_sort Ganguly, Sourik S.
collection PubMed
description Despite 35 years of clinical trials, there is little improvement in one-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg (c-Abl, Arg) are elevated in primary melanomas (60%), in a subset of benign nevi (33%), and in some human melanoma cell lines. Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is required for melanoma cell proliferation, survival, and invasion. Significantly, we identify the mechanism by which activated c-Abl promotes melanoma invasion by showing that it transcriptionally upregulates MMP-1, and using rescue approaches we demonstrate that c-Abl promotes invasion via a STAT3→MMP-1 pathway. Additionally, we show that c-Abl and Arg are not merely redundant, as active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Most importantly, c-Abl and Arg not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg kinase activity with the c-Abl/Arg inhibitor, nilotinib, dramatically inhibits metastasis in a mouse model. Taken together, these data identify c-Abl and Arg as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may useful in preventing metastasis in patients with melanomas harboring active c-Abl and Arg.
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spelling pubmed-32352412012-10-05 c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression Ganguly, Sourik S. Fiore, Leann S. Sims, Jonathan T. Friend, J. Woodrow Srinivasan, Divyamani Thacker, Matthew A. Cibull, Michael L. Wang, Chi Novak, Marian Kaetzel, David M. Plattner, Rina Oncogene Article Despite 35 years of clinical trials, there is little improvement in one-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg (c-Abl, Arg) are elevated in primary melanomas (60%), in a subset of benign nevi (33%), and in some human melanoma cell lines. Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is required for melanoma cell proliferation, survival, and invasion. Significantly, we identify the mechanism by which activated c-Abl promotes melanoma invasion by showing that it transcriptionally upregulates MMP-1, and using rescue approaches we demonstrate that c-Abl promotes invasion via a STAT3→MMP-1 pathway. Additionally, we show that c-Abl and Arg are not merely redundant, as active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Most importantly, c-Abl and Arg not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg kinase activity with the c-Abl/Arg inhibitor, nilotinib, dramatically inhibits metastasis in a mouse model. Taken together, these data identify c-Abl and Arg as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may useful in preventing metastasis in patients with melanomas harboring active c-Abl and Arg. 2011-09-05 2012-04-05 /pmc/articles/PMC3235241/ /pubmed/21892207 http://dx.doi.org/10.1038/onc.2011.361 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Ganguly, Sourik S.
Fiore, Leann S.
Sims, Jonathan T.
Friend, J. Woodrow
Srinivasan, Divyamani
Thacker, Matthew A.
Cibull, Michael L.
Wang, Chi
Novak, Marian
Kaetzel, David M.
Plattner, Rina
c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression
title c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression
title_full c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression
title_fullStr c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression
title_full_unstemmed c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression
title_short c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression
title_sort c-abl and arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235241/
https://www.ncbi.nlm.nih.gov/pubmed/21892207
http://dx.doi.org/10.1038/onc.2011.361
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