COPPER BINDING PROTEINS IN BREAST CANCER : CELLULAR AND MOLECULAR MECHANISMS
Doctoral thesis, 2023
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.
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.
Atox1
Memo1
cell migration
breast cancer
copper
ROS
KE-salen, Kemigården 4, Chalmers.
Opponent: Sharon Ruthstein, Bar Ilan University, Ramat Gan, Israel
Author
Xiaolu Zhang
Chalmers, Life Sciences, Chemical Biology
Memo1 binds reduced copper ions, interacts with copper chaperone Atox1, and protects against copper-mediated redox activity in vitro
Proceedings of the National Academy of Sciences of the United States of America,;Vol. 119(2022)p. e2206905119-
Journal article
Single-cell tracking demonstrates copper chaperone Atox1 to be required for breast cancer cell migration
Proceedings of the National Academy of Sciences of the United States of America,;Vol. 117(2020)p. 2014-2019
Journal article
The Caenorhabditis elegans homolog of human copper chaperone Atox1, CUC-1, aids in distal tip cell migration
Biometals,;Vol. 33(2020)p. 147-157
Journal article
Memo1 reduces copper-mediated reactive oxygen species in breast cancer cells
Cancer, the term alone, still creates fear in the hearts of many people. According to the World Health Organization (WHO), cancer is a major cause of death globally, accounting for one in six deaths worldwide. As a result, numerous studies have been conducted over the years to uncover the causes and treatment of cancer. One recent topic that has gained significant interest is the role of copper (Cu) in cancer.
Cu is an essential mineral for the maintaince of our health. Functions of our body, such as energy production, blood vessel formation, and gene activation, rely on Cu. In recent years, there has been growing interest in investigating the link between Cu and cancer. This interest is fueled by scientific evidence showing elevated Cu levels in many cancer cells. Cu levels are much higher than in normal cells in many types of cancer, such as breast, liver, and colon cancer. So, what's the possible link between Cu and cancer?
Cu cancer research is a rapidly evolving field. While much is still unknown about the link between Cu and cancer, scientists are exploring several avenues for exploiting regulating Cu levels in cells as a potential cancer treatment, and early studies show promise.
Previous studies indicate that Cu-binding proteins are implicated in cancer cell metastasis and viability. This thesis described that Memo1 is a Cu-binding protein and explores its prospective function in regulating the viability of breast cancer cells. Furthermore, this thesis also shows that the Cu-binding protein Atox1 and Memo1 and their possible interactions might affect breast cancer metastasis. In conclusion, this thesis provides some essential new molecular discoveries relevant to cancer. This could potentially lead to the development of cancer treatments that specifically target Cu-binding proteins and disrupt their ability to promote tumor growth. Further research is needed to better understand the mechanisms underlying the function of these Cu-binding proteins in cancer cells.
Cu is an essential mineral for the maintaince of our health. Functions of our body, such as energy production, blood vessel formation, and gene activation, rely on Cu. In recent years, there has been growing interest in investigating the link between Cu and cancer. This interest is fueled by scientific evidence showing elevated Cu levels in many cancer cells. Cu levels are much higher than in normal cells in many types of cancer, such as breast, liver, and colon cancer. So, what's the possible link between Cu and cancer?
Cu cancer research is a rapidly evolving field. While much is still unknown about the link between Cu and cancer, scientists are exploring several avenues for exploiting regulating Cu levels in cells as a potential cancer treatment, and early studies show promise.
Previous studies indicate that Cu-binding proteins are implicated in cancer cell metastasis and viability. This thesis described that Memo1 is a Cu-binding protein and explores its prospective function in regulating the viability of breast cancer cells. Furthermore, this thesis also shows that the Cu-binding protein Atox1 and Memo1 and their possible interactions might affect breast cancer metastasis. In conclusion, this thesis provides some essential new molecular discoveries relevant to cancer. This could potentially lead to the development of cancer treatments that specifically target Cu-binding proteins and disrupt their ability to promote tumor growth. Further research is needed to better understand the mechanisms underlying the function of these Cu-binding proteins in cancer cells.
Disease mechanisms of copper chaperone Atox1
Swedish Research Council (VR) (2019-03673), 2020-01-01 -- 2024-12-31.
Kopparjoners roll vid spridning av cancer
Cancerfonden (170708), 2018-01-01 -- 2020-12-31.
Role of copper chaperone Atox1 in breast cancer metastasis
Cancerfonden (200672PjF01H), 2021-01-01 -- 2023-12-31.
Mekanismer för kopparjontransport i mänskliga celler
Swedish Research Council (VR) (2015-03881), 2016-01-01 -- 2020-12-31.
Subject Categories
Biological Sciences
Health Sciences
Roots
Basic sciences
Areas of Advance
Life Science Engineering (2010-2018)
ISBN
978-91-7905-825-8
Doktorsavhandlingar vid Chalmers tekniska högskola. Ny serie: 5291
Publisher
Chalmers
KE-salen, Kemigården 4, Chalmers.
Opponent: Sharon Ruthstein, Bar Ilan University, Ramat Gan, Israel