Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells

Affordable Access

Download Read

Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells

Authors
  • Baldari, Silvia
  • Di Rocco, Giuliana
  • Heffern, Marie C.
  • Su, Timothy A.
  • Chang, Christopher J.
  • Toietta, Gabriele
Type
Published Article
Journal
Cancers
Publisher
MDPI AG
Publication Date
May 14, 2019
Volume
11
Issue
5
Identifiers
DOI: 10.3390/cancers11050659
PMID: 31083627
Source
MyScienceWork
Keywords
Funders
  • National Institutes of Health
License
Green

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 clonogenic 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.

Report this publication

Statistics

Seen <100 times
Downloaded <100 times