Effects of Copper Chelation on BRAF Positive Colon Carcinoma Cells.

Silvia Baldari, Giuliana Di Rocco, Marie C Heffern, Timothy A Su, Christopher J Chang, Gabriele Toietta

Effects of Copper Chelation on BRAF Positive Colon Carcinoma Cells.

Cancers (Basel) 2019 May 12;11(5). Epub 2019 May 12.

Department of Research, Advanced Diagnostic, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, via E. Chianesi 53, 00144 Rome, Italy.

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). 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 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 mutation compared to BRAF acting via differential phosphorylation levels of ERK1/2. Moreover, tetrathiomolybdate treatment was also effective in reducing the clonogenic potential of colon cancer BRAF 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 mutation.

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11050659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562624PMC
May 2019
16 Reads

Publication Analysis

Top Keywords

copper chelation
16
braf mutation
12
braf
10
bearing braf
8
cells bearing
8
effects copper
8
protein kinase
8
colon cancer
8
copper
6
kinase
6
cells
5
evaluated vitro
4
vitro vivo
4
vivo effects
4
metastatic cancers
4
properties evaluated
4
anti-angiogenic anti-inflammatory
4
anti-inflammatory properties
4
cancers anti-angiogenic
4
achieved pharmacological
4

References

(Supplied by CrossRef)

Similar Publications