The following study was conducted by Scientists from Chalmers University of Technology, Gothenburg, Sweden. Study is published in Proceedings of the National Academy of Sciences Journal as detailed below.
Proceedings of the National Academy of Sciences (2020); 117(4): 2014-2019
Single-cell Tracking Demonstrates Copper Chaperone Atox1 to be Required for Breast Cancer Cell Migration
Significance
Copper is an essential metal ion facilitating many biological functions. To avoid the toxicity of free copper, there are protein-based transport systems that deliver the metal to copper-dependent enzymes. Tumors have high demands for copper, but it is unclear why. Thus it is of importance to reveal copper-binding proteins involved in cancer progression. This work investigated the putative role of a copper-binding protein, Antioxidant 1 copper chaperone (Atox1), in breast cancer cell migration, which is a key step in cancer metastasis. We demonstrated that Atox1 is needed for efficient cell migration and identify partner proteins. Since primary breast tumors with high levels of Atox1 correlate with poorer patient survival, Atox1 may be a biomarker of metastatic breast cancer.
Abstract
Copper ions are needed for several hallmarks of cancer. However, the involved pathways, mechanisms, and copper-binding proteins are mostly unknown. We recently found that cytoplasmic Antioxidant 1 copper chaperone (Atox1), which is up-regulated in breast cancer, is localized at the lamellipodia edges of aggressive breast cancer cells. To reveal molecular insights into a putative role in cell migration, we here investigated breast cancer cell (MDA-MB-231) migration by video microscopy as a function of Atox1. Tracking of hundreds of individual cells (per condition) over a 9-h time series revealed that cell migration velocity and directionality are significantly reduced upon Atox1 silencing in the cells. Because silencing of the copper transporter ATP7A also reduced cell migration, these proteins appear to be on the same pathway, suggesting that their well-known copper transport activity is involved. In-cell proximity ligation assays demonstrated that Atox1, ATP7A, and the proenzyme of lysyl oxidase (LOX; copper-loaded via ATP7A) are all in close proximity and that LOX activity is reduced upon Atox1 silencing in the cells. Since LOX is an established player in cancer cell migration, our results imply that Atox1 mediates breast cancer cell migration via coordinated copper transport in the ATP7A-LOX axis. Because individual cell migration is an early step in breast cancer metastasis, Atox1 levels in tumor cells may be a predictive measure of metastasis potential and serve as a biomarker for copper depletion therapy.
Source:
Proceedings of the National Academy of Sciences
URL: https://www.pnas.org/content/117/4/2014
Citation:
Blockhuys, S., X. Zhang, et al. (2020). “Single-cell tracking demonstrates copper chaperone Atox1 to be required for breast cancer cell migration.” Proceedings of the National Academy of Sciences 117(4): 2014-2019.
