Metals and molecular carcinogenesis

Abstract

Many metals are essential for living organisms, but at higher doses they may be toxic and carcinogenic. Metal exposure occurs mainly in occupational settings and environmental contaminations in drinking water, air pollution and foods, which can result in serious health problems such as cancer. Arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr) and nickel (Ni) are classified as Group 1 carcinogens by the International Agency for Research on Cancer. This review provides a comprehensive summary of current concepts of the molecular mechanisms of metal-induced carcinogenesis and focusing on a variety of pathways, including genotoxicity, mutagenesis, oxidative stress, epigenetic modifications such as DNA methylation, histone post-translational modification and alteration in microRNA regulation, competition with essential metal ions and cancer-related signaling pathways. This review takes a broader perspective and aims to assist in guiding future research with respect to the prevention and therapy of metal exposure in human diseases including cancer.

Figure 1.

Arsenic reduced SLBP level and subsequent aberrant polyadenylation of canonical histone mRNA, leading to carcinogenesis. Canonical histone pre-mRNA is processed by a cleavage complex containing SLBP. Arsenic downregulates SLBP by promoting proteasomal degradation and epigenetically silencing SLBP gene, causing the polyadenylation of pre-mRNA of canonical histone mRNAs and resulting in increased stability. Polyadenylated canonical histones make more protein causing an imbalanced proportion of histone variants and displace non-canonical histone in the chromosome, leading to aberrant nucleosomal assembly and chromosome instability. A, poly-A tail. Figures are created with Biorender.com.

Figure 2.

Cd displaces Zn in the Zn-finger structure of a protein leading to altered protein conformation and activity. Cd can displace Zn due to their similarities in physical and chemical properties. Cd displaces Zn at the Zn-figure structure that contain two cysteines and two histidines. Altered orientation of the secondary structure will antagonize the activity of the wild-type protein. Cd, cadmium; Zn, zinc. Figures are created with Biorender.com.

Figure 3.

Cr(VI) reduction to Cr(III) in the cell will form Cr-DNA adducts. Cr(VI) is delivered into the cell via sulphate or phosphate anionic channels, and then reduced to intermediates Cr(V) and Cr(IV), and finally accumulates as Cr(III), the most stable form, which is able to form bulky DNA adducts with ligands such as GSH, cysteine and ascorbic acid to cause genotoxicity. Asc, ascorbic acid; Cr, chromium; Cys, cysteine. Figures are created with Biorender.com.

Figure 4.

Transport of particulate Ni compounds into the cell and delivery of Ni ions into the nucleus. Particulate Ni compounds (crystalline NiS and Ni₃S₂) enter cells by phagocytosis and subsequently release water-soluble Ni²⁺ ions within intracellular vacuoles. When vacuoles fused with lysosomes and acidified, Ni²⁺ ions are released into cytoplasm and then enter the nucleus to exert its toxic and carcinogenic effect. Water-soluble Ni compounds enter cells via active transport aided by surface metal transport proteins such as DMT-1. Amorphous Ni (NiS) is not taken by the cell due to its positive charge but changing its charge to negative will result in uptake and carcinogenesis. DMT-1, divalent metal transporter 1; Ni, nickel. Figures are created with Biorender.com.

Figure 5.

Ni displacing Fe in prolyl-hydroxylase and activating HIF signaling pathway. HIF can be hydroxylated by a class of prolyl-hydroxylase to be targeted for proteasomal degradation mediated by VHL. Ni can replace Fe from the enzyme and inhibit its activity, subsequently stabilizing HIF-1α and activating HIF signaling pathway. Fe, iron; Ni, nickel; VHL, von Hippel–Lindau. Figures are created with Biorender.com.