Regulatory roles of copper metabolism and cuproptosis in human cancers

Abstract

Copper is an essential micronutrient for human body and plays a vital role in various biological processes including cellular respiration and free radical detoxification. Generally, copper metabolism in the body is in a stable state, and there are specific mechanisms to regulate copper metabolism and maintain copper homeostasis. Dysregulation of copper metabolism may have a great connection with various types of diseases, such as Wilson disease causing copper overload and Menkes disease causing copper deficiency. Cancer presents high mortality rates in the world due to the unlimited proliferation potential, apoptosis escape and immune escape properties to induce organ failure. Copper is thought to have a great connection with cancer, such as elevated levels in cancer tissue and serum. Copper also affects tumor progression by affecting angiogenesis, metastasis and other processes. Notably, cuproptosis is a novel form of cell death that may provide novel targeting strategies for developing cancer therapy. Copper chelators and copper ionophores are two copper coordinating compounds for the treatment of cancer. This review will explore the relationship between copper metabolism and cancers, and clarify copper metabolism and cuproptosis for cancer targeted therapy.

Keywords: cancer; cancer therapeutics; copper; copper complexes; copper metabolism; cuproptosis.

Figure 1

A diagram of cellular copper transport and metabolism. Extracellularly, copper exists as Cu²⁺. The cellular reductases protein family Steap proteins (mainly Steap 2/3/4) reduce Cu²⁺ to Cu⁺, which is transported into the cell via Ctr1, and a fraction of Cu⁺ is targeted to cytosolic SOD1 by the copper chaperone CCS to scavenge free radicals. A fraction of Cu⁺ is delivered by the copper chaperone Cox17 to the mitochondrial Cox to generate ATP. A portion of Cu⁺ is delivered to ATP7A/B of the trans Golgi network by the copper chaperone Atox1, which promotes cuproproteins (CuPrs) assembly and secretion. The remaining excess Cu⁺ is sequestered by metallothionein (MT). There are copper sensors in the nucleus that respond to changes in copper concentration through regulating MT1 and MT2 gene transcriptions. In enterocytes, ATP7A migrates to the plasma membrane to pump Cu⁺ into the blood. In hepatocytes, ATP7B pumps Cu⁺ into the bile.

Figure 2

Survival curves for overall survival of high versus low expressing SLC31A1. (A) ACC, adrenocortical carcinoma; (B) BRCA, breast invasive carcinoma; (C) LGG, brain lower grade glioma; (D) MESO, mesothelioma. The overall survival rate of low expression of SLC31A1was significantly higher than that of high expression of SLC31A1. SLC31A1, solute carrier family 31 member 1 (copper ion transporter); HR, hazard rate. (http://gepia.cancer-pku.cn/index.html; Accessed 10 October 2022).

Figure 3

A diagram of the simple mechanism of cuproptosis. Elesclomol imports Cu²⁺ into the cell, and then reduced to Cu⁺ by FDX1. Cu⁺ binds to lipoylated components of the mitochondrial TCA cycle, promoting lipoylated protein aggregation followed by a decrease in iron-sulfur cluster proteins, thereby inducing proteotoxic stress, leading to cell death. ES, elesclomol; FDX1, ferredoxin 1; DLAT, dihydrolipoyl transacetylase; TCA, tricarboxylic acid cycle.