Copper is required for oncogenic BRAF signaling and tumorigenesis

Copper is required for oncogenic BRAF signaling and tumorigenesis

The BRAF kinase is mutated, typically V600E, to induce an active oncogenic state in a large fraction of melanoma, thyroid, hairy cell leukemia, and to a lesser extent, a wide spectrum of other cancers1,2. BRAFV600E phosphorylates and activates the kinases MEK1 and MEK2, which in turn phosphorylate a...

Full description

Bibliographic Details
Main Authors: Brady, Donita C., Crowe, Matthew S., Turski, Michelle L., Hobbs, G. Aaron, Yao, Xiaojie, Chaikuad, Apirat, Knapp, Stefan, Xiao, Kunhong, Campbell, Sharon L., Thiele, Dennis J., Counter, Christopher M.
Format: Online
Language:English
Published: 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138975/
id pubmed-4138975
recordtype oai_dc
spelling pubmed-41389752014-11-22 Copper is required for oncogenic BRAF signaling and tumorigenesis Brady, Donita C. Crowe, Matthew S. Turski, Michelle L. Hobbs, G. Aaron Yao, Xiaojie Chaikuad, Apirat Knapp, Stefan Xiao, Kunhong Campbell, Sharon L. Thiele, Dennis J. Counter, Christopher M. Article The BRAF kinase is mutated, typically V600E, to induce an active oncogenic state in a large fraction of melanoma, thyroid, hairy cell leukemia, and to a lesser extent, a wide spectrum of other cancers1,2. BRAFV600E phosphorylates and activates the kinases MEK1 and MEK2, which in turn phosphorylate and activate the kinases ERK1 and ERK2, stimulating the MAPK pathway to promote cancer3. Targeting MEK1/2 is proving to be an important therapeutic strategy, as a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma4, which is increased when co-administered with a BRAFV600E inhibitor5. In this regard, we previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu-MEK1 interaction6. We now show that genetic loss of the high affinity Cu transporter Ctr1 or mutations in MEK1 that disrupt Cu binding reduced BRAFV600E-driven signaling and tumorigenesis. Conversely, a MEK1-MEK5 chimera that phosphorylates ERK1/2 independent of Cu or an active ERK2 restored tumor growth to cells lacking Ctr1. Importantly, Cu chelators used in the treatment of Wilson disease7 reduced tumor growth of both BRAFV600E-transformed cells and cells resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat BRAFV600E mutation-positive cancers. 2014-04-09 2014-05-22 /pmc/articles/PMC4138975/ /pubmed/24717435 http://dx.doi.org/10.1038/nature13180 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download 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
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Brady, Donita C.
Crowe, Matthew S.
Turski, Michelle L.
Hobbs, G. Aaron
Yao, Xiaojie
Chaikuad, Apirat
Knapp, Stefan
Xiao, Kunhong
Campbell, Sharon L.
Thiele, Dennis J.
Counter, Christopher M.
spellingShingle Brady, Donita C.
Crowe, Matthew S.
Turski, Michelle L.
Hobbs, G. Aaron
Yao, Xiaojie
Chaikuad, Apirat
Knapp, Stefan
Xiao, Kunhong
Campbell, Sharon L.
Thiele, Dennis J.
Counter, Christopher M.
Copper is required for oncogenic BRAF signaling and tumorigenesis
author_facet Brady, Donita C.
Crowe, Matthew S.
Turski, Michelle L.
Hobbs, G. Aaron
Yao, Xiaojie
Chaikuad, Apirat
Knapp, Stefan
Xiao, Kunhong
Campbell, Sharon L.
Thiele, Dennis J.
Counter, Christopher M.
author_sort Brady, Donita C.
title Copper is required for oncogenic BRAF signaling and tumorigenesis
title_short Copper is required for oncogenic BRAF signaling and tumorigenesis
title_full Copper is required for oncogenic BRAF signaling and tumorigenesis
title_fullStr Copper is required for oncogenic BRAF signaling and tumorigenesis
title_full_unstemmed Copper is required for oncogenic BRAF signaling and tumorigenesis
title_sort copper is required for oncogenic braf signaling and tumorigenesis
description The BRAF kinase is mutated, typically V600E, to induce an active oncogenic state in a large fraction of melanoma, thyroid, hairy cell leukemia, and to a lesser extent, a wide spectrum of other cancers1,2. BRAFV600E phosphorylates and activates the kinases MEK1 and MEK2, which in turn phosphorylate and activate the kinases ERK1 and ERK2, stimulating the MAPK pathway to promote cancer3. Targeting MEK1/2 is proving to be an important therapeutic strategy, as a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma4, which is increased when co-administered with a BRAFV600E inhibitor5. In this regard, we previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu-MEK1 interaction6. We now show that genetic loss of the high affinity Cu transporter Ctr1 or mutations in MEK1 that disrupt Cu binding reduced BRAFV600E-driven signaling and tumorigenesis. Conversely, a MEK1-MEK5 chimera that phosphorylates ERK1/2 independent of Cu or an active ERK2 restored tumor growth to cells lacking Ctr1. Importantly, Cu chelators used in the treatment of Wilson disease7 reduced tumor growth of both BRAFV600E-transformed cells and cells resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat BRAFV600E mutation-positive cancers.
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138975/
_version_ 1613125862656311296

Similar Items