Copper chaperone ATOX1 is required for MAPK signaling and growth in BRAF mutation-positive melanoma
Year: 2019
Type: article
Abstract: Copper (Cu) is a tightly regulated micronutrient that functions as a structural or catalytic cofactor for specific proteins essential for a diverse array of biological processes. While the study of the extremely rare genetic diseases, Menkes and Wilson, has highlighted the requirement for proper Cu acquisition and elimination in biological systems for cellular growth and proliferation, the importance of dedicated Cu transport systems, like the Cu chaperones ATOX1 and CCS, in the pathophysiology of cancer is not well defined. We found that ATOX1 was significantly overexpressed in human blood, breast, and skin cancer samples, while CCS was significantly altered in human brain, liver, ovarian, and prostate cancer when compared to normal tissue. Further analysis of genetic expression data in Cancer Cell Line Encyclopedia (CCLE) revealed that ATOX1 is highly expressed in melanoma cell lines over other cancer cell lines. We previously found that Cu is required for BRAFV600E-driven MAPK signaling and melanomagenesis. Here we show that genetic loss of ATOX1 decreased BRAFV600E-dependent growth and signaling in human melanoma cell lines. Pharmacological inhibition of ATOX1 with a small molecule, DCAC50, decreased the phosphorylation of ERK1/2 and reduced the growth of BRAF mutation-positive melanoma cell lines in a dose-dependent manner. Taken together, these results suggest that targeting the Cu chaperone ATOX1 as a novel therapeutic angle in BRAFV600E-driven melanomas.
Source: Metallomics
DOI: 10.1039/c9mt00042a
Institution: University of Pennsylvania
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,653
Awards: G5881093318, G5988489043, G6032947000, Investigating paradoxical YAP activation as an emergent limitation to Cu chelation therapy in BRAF V600E-driven melanoma, Investigating the influence of copper on autophagy in pancreatic cancer, SPORE in Skin Cancer, Role of KLHL6 inactivation in mature B-cell malignancies, Molecular and Cellular Mechanisms of Copper-Dependent Nutrient Signaling and Metabolism
OpenAlex ID: W2957907911