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Title: Effects of Copper Chelation on BRAF V600E Positive Colon Carcinoma Cells

Abstract

High affinity copper binding to mitogen-activated protein kinase kinase 1 (MAP2K1, also known as MEK1) allosterically promotes the kinase activity of MEK1/2 on extracellular signal regulated kinases 1 and 2 (ERK1/2). Consequently, copper-dependent activation of the mitogen-activated (MAP) kinase pathway has a role in promoting tumor growth. Conversely, copper chelation may represent a possible therapeutic approach for a specific subset of tumors characterized by activating mutations in the serine/threonine protein kinase V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF), such as the V600E, occurring within the kinase domain (BRAF V600E). Tetrathiomolybdate (TM) is a specific copper chelating agent currently used for the treatment of Wilson’s disease and in preclinical studies for the management of metastatic cancers owing to its anti-angiogenic and anti-inflammatory properties. We evaluated in vitro and in vivo the effects of copper depletion achieved by pharmacological treatment with TM in human colorectal cells bearing the BRAF V600E mutation in comparison with BRAF wild type cells. We provide evidence that selective copper chelation differentially affects proliferation, survival and migration of colon cancer cells bearing the BRAF V600E mutation compared to BRAF wt acting via differential phosphorylation levels of ERK1/2. Moreover, tetrathiomolybdate treatment was also effective in reducing the clonogenicmore » potential of colon cancer BRAF V600E cells resistant to BRAF pharmacological inhibition. In conclusion, these results support further assessment of copper chelation therapy as an adjuvant therapy for inhibiting the progression of colon cancers containing the BRAF V600E mutation.« less

Authors:
 [1];  [1]; ORCiD logo [2]; ORCiD logo [3]; ORCiD logo [3]; ORCiD logo [1]
  1. RCCS Regina Elena National Cancer Inst., Rome (Italy)
  2. Univ. of California, Davis, CA (United States); Univ. of California, Berkeley, CA (United States)
  3. Univ. of California, Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1572008
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Cancers (Basel)
Additional Journal Information:
Journal Name: Cancers (Basel); Journal Volume: 11; Journal Issue: 5; Journal ID: ISSN 2072-6694
Publisher:
MDPI
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; copper; colon cancer; BRAF; tetrathiomolybdate; chelating agents; mitogen-activated protein kinase; BRAFV600E mutation

Citation Formats

Baldari, Silvia, Di Rocco, Giuliana, Heffern, Marie C., Su, Timothy A., Chang, Christopher J., and Toietta, Gabriele. Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells. United States: N. p., 2019. Web. doi:10.3390/cancers11050659.
Baldari, Silvia, Di Rocco, Giuliana, Heffern, Marie C., Su, Timothy A., Chang, Christopher J., & Toietta, Gabriele. Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells. United States. doi:10.3390/cancers11050659.
Baldari, Silvia, Di Rocco, Giuliana, Heffern, Marie C., Su, Timothy A., Chang, Christopher J., and Toietta, Gabriele. Sun . "Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells". United States. doi:10.3390/cancers11050659. https://www.osti.gov/servlets/purl/1572008.
@article{osti_1572008,
title = {Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells},
author = {Baldari, Silvia and Di Rocco, Giuliana and Heffern, Marie C. and Su, Timothy A. and Chang, Christopher J. and Toietta, Gabriele},
abstractNote = {High affinity copper binding to mitogen-activated protein kinase kinase 1 (MAP2K1, also known as MEK1) allosterically promotes the kinase activity of MEK1/2 on extracellular signal regulated kinases 1 and 2 (ERK1/2). Consequently, copper-dependent activation of the mitogen-activated (MAP) kinase pathway has a role in promoting tumor growth. Conversely, copper chelation may represent a possible therapeutic approach for a specific subset of tumors characterized by activating mutations in the serine/threonine protein kinase V-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF), such as the V600E, occurring within the kinase domain (BRAFV600E). Tetrathiomolybdate (TM) is a specific copper chelating agent currently used for the treatment of Wilson’s disease and in preclinical studies for the management of metastatic cancers owing to its anti-angiogenic and anti-inflammatory properties. We evaluated in vitro and in vivo the effects of copper depletion achieved by pharmacological treatment with TM in human colorectal cells bearing the BRAFV600E mutation in comparison with BRAF wild type cells. We provide evidence that selective copper chelation differentially affects proliferation, survival and migration of colon cancer cells bearing the BRAFV600E mutation compared to BRAFwt acting via differential phosphorylation levels of ERK1/2. Moreover, tetrathiomolybdate treatment was also effective in reducing the clonogenic potential of colon cancer BRAFV600E cells resistant to BRAF pharmacological inhibition. In conclusion, these results support further assessment of copper chelation therapy as an adjuvant therapy for inhibiting the progression of colon cancers containing the BRAFV600E mutation.},
doi = {10.3390/cancers11050659},
journal = {Cancers (Basel)},
number = 5,
volume = 11,
place = {United States},
year = {2019},
month = {5}
}

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