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. 2024 Jul;75(1):1-6.
doi: 10.3164/jcbn.24-14. Epub 2024 Apr 6.

Role of copper and SOD3-mediated extracellular redox regulation in tumor progression

Tetsuro Kamiya  1
Affiliations

Role of copper and SOD3-mediated extracellular redox regulation in tumor progression

Tetsuro Kamiya. J Clin Biochem Nutr. 2024 Jul.

Abstract

Copper (Cu), an essential micronutrient, participates in several physiological processes, including cell proliferation and development. Notably, the disturbance of Cu homeostasis promotes tumor progression through the generation of oxidative stress. Chronic or excessive accumulation of reactive oxygen species (ROS) causes lipid peroxidation, protein denaturation, and enzyme inactivation, which leads to a breakdown of intracellular homeostasis and exacerbates tumor progression. The disruption of the ROS scavenging mechanism also reduces resistance to oxidative stress, leading to further deterioration in a disease state, and maintenance of redox homeostasis is thought to inhibit the onset and progression of various diseases. Superoxide dismutase 3 (SOD3), a Cu-containing secretory antioxidative enzyme, plays a key role in extracellular redox regulation, and the significant reduction in SOD3 facilitates tumor progression. Furthermore, the significant induction of SOD3 participates in tumor metastasis. This review focuses on the role of Cu homeostasis and antioxidative enzymes, including SOD3, in tumor progression, to help clarify the role of redox regulation.

Keywords: copper; glutathione; reactive oxygen species; superoxide dismutase 3; tumor.

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Conflict of interest statement

No potential conflicts of interest were disclosed.

Figures

Fig. 1.
Fig. 1.
Involvement of N-glycosylation in SOD3 secretion. SOD3 receives Cu from ATP7A in the trans-Golgi network. N-glycosylation, especially FUT8-mediated fucosylation, plays a critical role in SOD3 secretion to extracellular spaces. In addition, non-fucosylated SOD3 does not show antioxidative properties. Cleaved- and R213G mutated-SOD3 are secreted in extracellular spaces, but they cannot bind to heparan sulfate because they do not have the conserved heparin-binding domain. Accordingly, their serum concentrations drastically increase compared with uncleaved or wildtype SOD3.
Fig. 2.
Fig. 2.
GSH facilitates Cu-mediated cell growth. Mitochondrial, NADPH oxidase, or metabolic enzyme-mediated ROS accumulation induces SLC7A11 expression through the activation of Nrf2.tif. SLC7A11 increases intracellular GSH by promoting cystine uptake. Excess accumulation of Cu is observed in several tumor cells, and Cu also induces SLC7A11 expression. Increased GSH protects the cells from the damaging effects of ROS and participates in Cu detoxification by binding to Cu, which leads to Cu-mediated cell growth and tumor progression. GSSG, oxidized-GSH.
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