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Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells

1
Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy
2
Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA
3
Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
4
Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(5), 659; https://doi.org/10.3390/cancers11050659
Received: 13 March 2019 / Revised: 7 May 2019 / Accepted: 9 May 2019 / Published: 12 May 2019
(This article belongs to the Special Issue Colorectal Cancers)
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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 (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. View Full-Text
Keywords: copper; colon cancer; BRAF; tetrathiomolybdate; chelating agents; mitogen-activated protein kinase; BRAFV600E mutation copper; colon cancer; BRAF; tetrathiomolybdate; chelating agents; mitogen-activated protein kinase; BRAFV600E mutation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Baldari, S.; Di Rocco, G.; Heffern, M.C.; Su, T.A.; Chang, C.J.; Toietta, G. Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells. Cancers 2019, 11, 659.

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