Back to Search
Start Over
Copper chaperone ATOX1 is required for MAPK signaling and growth in BRAF mutation-positive melanoma
- Source :
- Metallomics. 11:1430-1440
- Publication Year :
- 2019
- Publisher :
- Oxford University Press (OUP), 2019.
-
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.
- Subjects :
- Proto-Oncogene Proteins B-raf
0301 basic medicine
Skin Neoplasms
MAP Kinase Signaling System
Biophysics
Biochemistry
Article
Biomaterials
ATOX1
03 medical and health sciences
Prostate cancer
Copper Transport Proteins
Cell Line, Tumor
medicine
Humans
Point Mutation
Melanoma
030102 biochemistry & molecular biology
biology
Cell growth
Chemistry
Metals and Alloys
medicine.disease
Up-Regulation
Gene Expression Regulation, Neoplastic
030104 developmental biology
Chemistry (miscellaneous)
Cell culture
Chaperone (protein)
biology.protein
Cancer research
Phosphorylation
Skin cancer
Gene Deletion
Molecular Chaperones
Subjects
Details
- ISSN :
- 1756591X and 17565901
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Metallomics
- Accession number :
- edsair.doi.dedup.....3eeacb73171dc5b5fbf0ba9291bcb1b7