Xiaolu Zhang, Kemisk Biologi

​​​​​Fakultetsopponent: Professor Sharon Ruthstein, Bar Ilan University, Ramat Gan, Israel

Handledare: Professor Pernilla Wittung Stafshede, Chalmers
Examinator: Professor Fredrik Westerlund, Chalmers

Sammanfattning:

Cancer is one of the leading causes of human death. However, the mechanisms governing cancer are still not fully understood. Elevated levels of copper (Cu) have been observed in both cancerous tissues and the serum of cancer patients. Cu ions play a crucial role in supporting cancer by activating Cu-dependent enzymes, which promote cancer cell proliferation, angiogenesis, and metastasis. Cu ions can undergo redox reactions, switching between the +1 and +2 oxidation states. Free Cu ions can therefore catalyze the production of reactive oxygen species (ROS), which may damage biomolecules. To avoid such reactions, Cu ions are controlled and transported by dedicated Cu transport proteins in cells.

This thesis focuses on two Cu-binding proteins, antioxidant 1 Cu chaperone (Atox1) and mediator of cell motility 1 (Memo1). Previous studies have shown that Atox1 is upregulated in breast cancer cells and patients. The results of Paper I indicate that Atox1 knockdown significantly reduces the velocity and directionality of breast cancer cell migration. Data in Paper I also show close proximity between Atox1 and the Cu-dependent enzyme lysyl oxidase (LOX) in cells. These results imply that Cu transport in the Atox1-ATP7A-LOX axis is crucial for cancer cell migration. I also investigated the role of an Atox1 homolog, CUC-1, in Caenorhabditis elegans (C. elegans) cell migration during development (Paper II). CUC-1 knock-out worms have more developmental defects, implying that Atox1-like proteins contribute to cell migration during development.

Memo1, connected to many oncogenic signaling pathways, was recently suggested to bind oxidized Cu ions and promote ROS generation. In contrast, my work shows that Memo1 binds the reduced form of Cu and protects against Cu-induced ROS generation in vitro and in breast cancer cells (Paper III and IV). Memo1 knockdown and external Cu addition significantly decrease cell viability and increase ROS levels in breast cancer cells. This Memo1 functionality may serve as a protective mechanism, allowing cancer cells to handle the increased demand of Cu ions in cancer-related processes.

In conclusion, my research provides important new discoveries for the Cu-binding proteins Atox1 and Memo1 that may be relevant for future cancer treatments.