Copper and Colorectal Cancer

Abstract

Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30-40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is crucial for mitochondrial respiration, pigmentation, iron transport, antioxidant defense, hormone production, and extracellular matrix biosynthesis. Copper deficiency, often caused by mutations in the ATP7A gene, results in Menkes disease, an X-linked recessive disorder. On the contrary, Wilson disease is characterized by toxic copper accumulation. Cuproptosis, a unique form of cell death regulated by copper, is a subtype of necrosis induced by enhanced mitochondrial metabolism and intracellular copper accumulation. This process can reduce the malignant potential of tumor cells by inhibiting glucose metabolism. Therapeutically, copper and its complexes have shown efficacy in malignancy treatments. The disruption of copper homeostasis and excessive cuproplasia are significant in colorectal cancer development and metastasis. Therefore, manipulating copper status presents a potential therapeutic target for colorectal cancer, using copper chelators to inhibit copper formation or copper ion carriers to promote cuproptosis. This review highlights the role of copper in human physiology and pathology, emphasizing its impact on colorectal cancer and potential therapeutic strategies. Future AI-based approaches are anticipated to accelerate the development of new compounds targeting cuproptosis and copper disruption in colorectal cancer.

Keywords: colorectal cancer; copper metabolism; cuproplasia; cuproptosis.

Figure 1

Role of copper in colorectal cancer development. ATOX, Antioxidant-protein 1; SOD1, Super oxide dismutase 1; SOD3, Super oxide dismutase 3; ROS, Reactive oxygen species; SLC31A1, Solute Carrier Family 31 member 1; SCO1, Synthesis of Cytochrome C Oxidase 1; COX11, Cytochrome C Copper Chaperone 11; CRC, colorectal cancer; ATP7A, P-type ATPase; ATP, Adenosine triphosphate; IL-17, Interleukin-17, STEP4, Six-transmembrane epithelial antigen of prostate 4; XIAP, X-linked inhibitor of apoptosis; NFkB, Nuclear factor kappa B. Created in BioRender.com.