Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells

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

doi:10.3390/cancers11050659

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

Journal Article · Sun May 12 00:00:00 EDT 2019 · Cancers (Basel)

DOI:https://doi.org/10.3390/cancers11050659· OSTI ID:1572008

Baldari, Silvia ^[1]; Di Rocco, Giuliana ^[1];

^[2];

^[3];

^[1]

RCCS Regina Elena National Cancer Inst., Rome (Italy)
Univ. of California, Davis, CA (United States); Univ. of California, Berkeley, CA (United States)
Univ. of California, Berkeley, CA (United States)

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.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1572008

Journal Information:: Cancers (Basel), Vol. 11, Issue 5; ISSN 2072-6694

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

Citation Metrics:

Cited by: 22 works

Citation information provided by
Web of Science

References (64)

Spherical Cancer Models in Tumor Biology Weiswald, Louis-Bastien; Bellet, Dominique; Dangles-Marie, Virginie Neoplasia, Vol. 17, Issue 1 https://doi.org/10.1016/j.neo.2014.12.004	journal	January 2015
Copper and Angiogenesis: Unravelling a Relationship key to Cancer Progression Finney, Lydia; Vogt, Stefan; Fukai, Tohru Clinical and Experimental Pharmacology and Physiology, Vol. 36, Issue 1 https://doi.org/10.1111/j.1440-1681.2008.04969.x	journal	January 2009
Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF Wan, Paul T. C.; Garnett, Mathew J.; Roe, S. Mark Cell, Vol. 116, Issue 6 https://doi.org/10.1016/S0092-8674(04)00215-6	journal	March 2004
ColonyArea: An ImageJ Plugin to Automatically Quantify Colony Formation in Clonogenic Assays Guzmán, Camilo; Bagga, Manish; Kaur, Amanpreet PLoS ONE, Vol. 9, Issue 3 https://doi.org/10.1371/journal.pone.0092444	journal	March 2014
Copper deficiency as an anti-cancer strategy. Goodman, V. L.; Brewer, G. J.; Merajver, S. D. Endocrine-related cancer https://doi.org/10.1677/erc.0.0110255	journal	June 2004
Management of colorectal cancer Stintzing, Sebastian F1000Prime Reports, Vol. 6 https://doi.org/10.12703/P6-108	journal	November 2014
Mutations of the BRAF gene in human cancer Davies, Helen; Bignell, Graham R.; Cox, Charles Nature, Vol. 417, Issue 6892 https://doi.org/10.1038/nature00766	journal	June 2002
A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer Gartner, Elaina M.; Griffith, Kent A.; Pan, Quintin Investigational New Drugs, Vol. 27, Issue 2 https://doi.org/10.1007/s10637-008-9165-9	journal	August 2008
Apoptosis induced by a HIPK2 full-length-specific siRNA is due to off-target effects rather than prevalence of HIPK2-Δe8 isoform Di Rocco, Giuliana; Verdina, Alessandra; Gatti, Veronica Oncotarget, Vol. 7, Issue 2 https://doi.org/10.18632/oncotarget.6423	journal	November 2015
Turning Tumor-Promoting Copper into an Anti-Cancer Weapon via High-Throughput Chemistry Wang, F.; Jiao, P.; Qi, M. Current Medicinal Chemistry, Vol. 17, Issue 25 https://doi.org/10.2174/092986710791859315	journal	September 2010
Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF -Mutated Colorectal Cancer Kopetz, Scott; Desai, Jayesh; Chan, Emily Journal of Clinical Oncology, Vol. 33, Issue 34 https://doi.org/10.1200/JCO.2015.63.2497	journal	December 2015
Transcriptome analysis of copper homeostasis genes reveals coordinated upregulation of SLC31A1 , SCO 1, and COX11 in colorectal cancer Barresi, Vincenza; Trovato-Salinaro, Angela; Spampinato, Giorgia FEBS Open Bio, Vol. 6, Issue 8 https://doi.org/10.1002/2211-5463.12060	journal	July 2016
Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species Fatfat, Maamoun; Merhi, Raghida Abou; Rahal, Omar BMC Cancer, Vol. 14, Issue 1 https://doi.org/10.1186/1471-2407-14-527	journal	July 2014
Is copper chelation an effective anti-angiogenic strategy for cancer treatment? Antoniades, V.; Sioga, A.; Dietrich, E. M. Medical Hypotheses, Vol. 81, Issue 6 https://doi.org/10.1016/j.mehy.2013.09.035	journal	December 2013
Cancer Therapy With Tetrathiomolybdate: Antiangiogenesis by Lowering Body Copper—A Review Brewer, George J.; Merajver, Sofia D. Integrative Cancer Therapies, Vol. 1, Issue 4 https://doi.org/10.1177/1534735402238185	journal	December 2002
Copper-binding compounds as proteasome inhibitors and apoptosis inducers in human cancer Daniel, Kenyon, G. Frontiers in Bioscience, Vol. 12, Issue 1 https://doi.org/10.2741/2054	journal	January 2007
Phase II Trial of Copper Depletion with Tetrathiomolybdate as an Antiangiogenesis Strategy in Patients with Hormone-Refractory Prostate Cancer Henry, N. Lynn; Dunn, Rodney; Merjaver, Sofia Oncology, Vol. 71, Issue 3-4 https://doi.org/10.1159/000106066	journal	January 2006
The role of copper in drug-resistant murine and human tumors Majumder, S.; Chatterjee, S.; Pal, Smarajit BioMetals, Vol. 22, Issue 2 https://doi.org/10.1007/s10534-008-9174-3	journal	October 2008
Copper Chelation Inhibits BRAF ^V600E -Driven Melanomagenesis and Counters Resistance to BRAF ^V600E and MEK1/2 Inhibitors Brady, Donita C.; Crowe, Matthew S.; Greenberg, Danielle N. Cancer Research, Vol. 77, Issue 22 https://doi.org/10.1158/0008-5472.CAN-16-1190	journal	October 2017
Copper is required for oncogenic BRAF signalling and tumorigenesis Brady, Donita C.; Crowe, Matthew S.; Turski, Michelle L. Nature, Vol. 509, Issue 7501 https://doi.org/10.1038/nature13180	journal	April 2014
Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations Dankner, Matthew; Rose, April A. N.; Rajkumar, Shivshankari Oncogene, Vol. 37, Issue 24 https://doi.org/10.1038/s41388-018-0171-x	journal	March 2018
A Novel Role for Copper in Ras/Mitogen-Activated Protein Kinase Signaling Turski, M. L.; Brady, D. C.; Kim, H. J. Molecular and Cellular Biology, Vol. 32, Issue 7 https://doi.org/10.1128/MCB.05722-11	journal	January 2012
Elevated copper and oxidative stress in cancer cells as a target for cancer treatment Gupte, Anshul; Mumper, Russell J. Cancer Treatment Reviews, Vol. 35, Issue 1 https://doi.org/10.1016/j.ctrv.2008.07.004	journal	February 2009
Influencing the Tumor Microenvironment: A Phase II Study of Copper Depletion Using Tetrathiomolybdate in Patients with Breast Cancer at High Risk for Recurrence and in Preclinical Models of Lung Metastases Chan, Nancy; Willis, Amy; Kornhauser, Naomi Clinical Cancer Research, Vol. 23, Issue 3 https://doi.org/10.1158/1078-0432.CCR-16-1326	journal	October 2016
Resistant mechanisms to BRAF inhibitors in melanoma Manzano, José Luís; Layos, Laura; Bugés, Cristina Annals of Translational Medicine, Vol. 4, Issue 12 https://doi.org/10.21037/atm.2016.06.07	journal	June 2016
Mitogen-activated protein kinase (MEK) inhibitors to treat melanoma alone or in combination with other kinase inhibitors Faghfuri, Elnaz; Nikfar, Shekoufeh; Niaz, Kamal Expert Opinion on Drug Metabolism & Toxicology, Vol. 14, Issue 3 https://doi.org/10.1080/17425255.2018.1432593	journal	January 2018
Resistance to BRAF Inhibition in BRAF-Mutant Colon Cancer Can Be Overcome with PI3K Inhibition or Demethylating Agents Mao, M.; Tian, F.; Mariadason, J. M. Clinical Cancer Research, Vol. 19, Issue 3 https://doi.org/10.1158/1078-0432.CCR-11-1446	journal	December 2012
BRAF inhibitors: the current and the future Zhang, Weijiang Current Opinion in Pharmacology, Vol. 23 https://doi.org/10.1016/j.coph.2015.05.015	journal	August 2015
Genetic alterations in main candidate genes during melanoma progression Sini, Maria Cristina; Doneddu, Valentina; Paliogiannis, Panagiotis Oncotarget, Vol. 9, Issue 9 https://doi.org/10.18632/oncotarget.23989	journal	January 2018
Pre-operative chemoradiation followed by post-operative adjuvant therapy with tetrathiomolybdate, a novel copper chelator, for patients with resectable esophageal cancer Schneider, Bryan J.; Lee, Julia Shin-Jung; Hayman, James A. Investigational New Drugs, Vol. 31, Issue 2 https://doi.org/10.1007/s10637-012-9864-0	journal	July 2012
In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease Heffern, Marie C.; Park, Hyo Min; Au-Yeung, Ho Yu Proceedings of the National Academy of Sciences, Vol. 113, Issue 50 https://doi.org/10.1073/pnas.1613628113	journal	November 2016
Multi-omics of 34 colorectal cancer cell lines - a resource for biomedical studies Berg, Kaja C. G.; Eide, Peter W.; Eilertsen, Ina A. Molecular Cancer, Vol. 16, Issue 1 https://doi.org/10.1186/s12943-017-0691-y	journal	July 2017
Control of Copper Status for Cancer Therapy Goodman, Vicki; Brewer, George; Merajver, Sofia Current Cancer Drug Targets, Vol. 5, Issue 7 https://doi.org/10.2174/156800905774574066	journal	November 2005
Copper chelation in cancer therapy using tetrathiomolybdate: an evolving paradigm Khan, Gazala; Merajver, Sofia Expert Opinion on Investigational Drugs, Vol. 18, Issue 4 https://doi.org/10.1517/13543780902845622	journal	April 2009
Copper suppression as cancer therapy: the rationale for copper chelating agents in BRAF ^V600 mutated melanoma Sammons, Sarah; Brady, Donita; Vahdat, Linda Melanoma Management, Vol. 3, Issue 3 https://doi.org/10.2217/mmt-2015-0005	journal	September 2016
Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation Vinci, Maria; Gowan, Sharon; Boxall, Frances BMC Biology, Vol. 10, Issue 1 https://doi.org/10.1186/1741-7007-10-29	journal	January 2012
Bioavailable copper modulates oxidative phosphorylation and growth of tumors Ishida, S.; Andreux, P.; Poitry-Yamate, C. Proceedings of the National Academy of Sciences, Vol. 110, Issue 48 https://doi.org/10.1073/pnas.1318431110	journal	November 2013
Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse Jain, S.; Cohen, J.; Ward, M. M. Annals of Oncology, Vol. 24, Issue 6 https://doi.org/10.1093/annonc/mds654	journal	February 2013
Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation Chapman, Paul B.; Hauschild, Axel; Robert, Caroline New England Journal of Medicine, Vol. 364, Issue 26 https://doi.org/10.1056/NEJMoa1103782	journal	June 2011
Emerging treatment options for BRAF-mutant colorectal cancer Ursem, Carling; Atreya, Chloe E.; Van Loon, Katherine Gastrointestinal Cancer: Targets and Therapy, Vol. Volume 8 https://doi.org/10.2147/GICTT.S125940	journal	January 2018
The Role of Copper in Tumour Angiogenesis Lowndes, Sarah A.; Harris, Adrian L. Journal of Mammary Gland Biology and Neoplasia, Vol. 10, Issue 4 https://doi.org/10.1007/s10911-006-9003-7	journal	October 2005
In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro Liang, Chun-Chi; Park, Ann Y.; Guan, Jun-Lin Nature Protocols, Vol. 2, Issue 2 https://doi.org/10.1038/nprot.2007.30	journal	February 2007
Epigenetic and genetic features of 24 colon cancer cell lines Ahmed, D.; Eide, P. W.; Eilertsen, I. A. Oncogenesis, Vol. 2, Issue 9 https://doi.org/10.1038/oncsis.2013.35	journal	September 2013
Inhibition of the Growth of Squamous Cell Carcinoma by Tetrathiomolybdate-Induced Copper Suppression in a Murine Model Cox, Claudell; Merajver, Sofia D.; Yoo, Sirius Archives of Otolaryngology–Head & Neck Surgery, Vol. 129, Issue 7 https://doi.org/10.1001/archotol.129.7.781	journal	July 2003
Repositioning the Old, Existing Copper-Binding Drugs for Cancer Treatment Dou, Q. Ping Clinical and Experimental Pharmacology, Vol. 02, Issue 01 https://doi.org/10.4172/2161-1459.1000e102	journal	January 2012
Copper Transport Systems are Involved in Multidrug Resistance and Drug Transport Furukawa, Tatsuhiko; Komatsu, Masaharu; Ikeda, Ryuji Current Medicinal Chemistry, Vol. 15, Issue 30 https://doi.org/10.2174/092986708786848479	journal	December 2008
Serum and tissue trace elements in colorectal cancer Gupta, Sanjeev K.; Shukla, Vijay K.; Vaidya, Madho P. Journal of Surgical Oncology, Vol. 52, Issue 3 https://doi.org/10.1002/jso.2930520311	journal	March 1993
Copper is required for oncogenic BRAF signalling and tumorigenesis Stefan, Knapp,; Xiaojie, Yao,; M., Counter, Christopher The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/hcaw-fj23	text	January 2014
Analysis Of Biodistribution And Engraftment Into The Liver Of Genetically Modified Mesenchymal Stromal Cells Derived From Adipose Tissue. Di Rocco, Giuliana; Gentile, Antonietta; Antonini, Annalisa Zenodo https://doi.org/10.5281/zenodo.812259	text	January 2017
Apoptosis Induced By A Hipk2 Full-Length-Specific Sirna Is Due To Off-Target Effects Rather Than Prevalence Of Hipk2-Δe8 Isoform Di Rocco, Giuliana; Verdina, Alessandra; Gatti, Ilaria Zenodo https://doi.org/10.5281/zenodo.813004	text	January 2017
Management of colorectal cancer Winslet, Mark Surgical Oncology, Vol. 6, Issue 4 https://doi.org/10.1016/s0960-7404(98)00005-x	journal	December 1997
Improved survival with vemurafenib in melanoma with BRAF V600E mutation Chapman, P. B.; Hauschild, A.; Robert, C. Massachusetts Medical Society https://doi.org/10.5167/uzh-48844	text	January 2011
Analysis Of Biodistribution And Engraftment Into The Liver Of Genetically Modified Mesenchymal Stromal Cells Derived From Adipose Tissue. Di Rocco, Giuliana; Gentile, Antonietta; Antonini, Annalisa Zenodo https://doi.org/10.5281/zenodo.812260	text	January 2017
Management of Colorectal Cancer Cassidy, J. British Journal of Cancer, Vol. 78, Issue 11 https://doi.org/10.1038/bjc.1998.720	journal	December 1998
UV Radiation-induced Impairment of Cellular Morphology and Motility is Enhanced by DUSP3/VHR Loss and FAK Activation Pereira, Nadine Ranieri; Russo, Lilian Cristina; Forti, Fabio Luis Cell Biochemistry and Biophysics, Vol. 79, Issue 2 https://doi.org/10.1007/s12013-021-00966-1	journal	January 2021
Serum iron, copper and zinc concentrations and risk of cancer mortality in US adults Wu, T. Annals of Epidemiology, Vol. 14, Issue 3 https://doi.org/10.1016/s1047-2797(03)00119-4	journal	March 2004
Targeting copper in cancer therapy: ‘Copper That Cancer’ Denoyer, Delphine; Masaldan, Shashank; La Fontaine, Sharon Metallomics, Vol. 7, Issue 11 https://doi.org/10.1039/c5mt00149h	journal	January 2015
An Integrated Computational/Experimental Model of Tumor Invasion Frieboes, Hermann B.; Zheng, Xiaoming; Sun, Chung-Ho Cancer Research, Vol. 66, Issue 3 https://doi.org/10.1158/0008-5472.can-05-3166	journal	February 2006
BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression Barras, David; Missiaglia, Edoardo; Wirapati, Pratyaksha Clinical Cancer Research, Vol. 23, Issue 1 https://doi.org/10.1158/1078-0432.ccr-16-0140	journal	June 2016
Copper Chelation as Targeted Therapy in a Mouse Model of Oncogenic BRAF-Driven Papillary Thyroid Cancer Xu, MengMeng; Casio, Michael; Range, Danielle E. Clinical Cancer Research, Vol. 24, Issue 17 https://doi.org/10.1158/1078-0432.ccr-17-3705	journal	July 2018
Correction: Influencing the Tumor Microenvironment: A Phase II Study of Copper Depletion Using Tetrathiomolybdate in Patients with Breast Cancer at High Risk for Recurrence and in Preclinical Models of Lung Metastases Chan, Nancy; Willis, Amy; Kornhauser, Naomi Clinical Cancer Research, Vol. 26, Issue 18 https://doi.org/10.1158/1078-0432.ccr-20-3177	journal	September 2020
Hitting the Target in BRAF-Mutant Colorectal Cancer Nagaraja, Ankur K.; Bass, Adam J. Journal of Clinical Oncology, Vol. 33, Issue 34 https://doi.org/10.1200/jco.2015.63.7793	journal	December 2015
Tetrathiomolybdate Is Partially Protective Against Hyperglycemia in Rodent Models of Diabetes Zeng, Chunhua; Hou, Guoqing; Dick, Robert Experimental Biology and Medicine, Vol. 233, Issue 8 https://doi.org/10.3181/0801-rm-10	journal	August 2008
Analysis of Biodistribution and Engraftment into the Liver of Genetically Modified Mesenchymal Stromal Cells Derived from Adipose Tissue Di Rocco, Giuliana; Gentile, Antonietta; Antonini, Annalisa Cell Transplantation, Vol. 21, Issue 9 https://doi.org/10.3727/096368911x637452	journal	September 2012

Similar Records

AKT is critically involved in the antagonism of BRAF inhibitor sorafenib against dabrafenib in colorectal cancer cells harboring both wild-type and mutant (V600E) BRAF genes

Journal Article · Sat Jul 15 00:00:00 EDT 2017 · Biochemical and Biophysical Research Communications · OSTI ID:1572008

Wang, Hongbin; Quan, Haitian; Lou, Liguang

Chemically Linked Vemurafenib Inhibitors Promote an Inactive BRAF^V600E Conformation

Journal Article · Thu Aug 25 00:00:00 EDT 2016 · ACS Chemical Biology · OSTI ID:1572008

Grasso, Michael; Estrada, Michelle A.; Ventocilla, Christian; +5 more

The BRAF{sup T1799A} mutation confers sensitivity of thyroid cancer cells to the BRAF{sup V600E} inhibitor PLX4032 (RG7204)

Journal Article · Fri Jan 28 00:00:00 EST 2011 · Biochemical and Biophysical Research Communications · OSTI ID:1572008

Xing, Joanna; Liu, Ruixin; Xing, Mingzhao; +1 more

Related Subjects

60 APPLIED LIFE SCIENCES
copper
colon cancer
BRAF
tetrathiomolybdate
chelating agents
mitogen-activated protein kinase
BRAFV600E mutation

Title: Effects of Copper Chelation on BRAFV600E Positive Colon Carcinoma Cells

Citation Formats

References (64)

Similar Records

Related Subjects

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