Metals and Mechanisms of Carcinogenesis

Abstract

Metal exposure is pervasive and not limited to sporadic poisoning events or toxic waste sites. Hundreds of millions of people around the globe are affected by chronic metal exposure, which is associated with serious health concerns, including cancer, as demonstrated in a variety of studies at the molecular, systemic, and epidemiologic levels. Metal-induced toxicity and carcinogenicity are sophisticated and complex in nature. This review provides a broad context and holistic view of currently available studies on the mechanisms of metal-induced carcinogenesis. Specifically, we focus on the five most prevalent carcinogenic metals, arsenic, nickel, cadmium, chromium, and beryllium, and their potential to drive carcinogenesis in humans. A comprehensive understanding of the mechanisms behind the development of metal-induced cancer can provide valuable insights for therapeutic intervention involving molecular targets in metal-induced carcinogenesis.

Keywords: carcinogenesis; epigenetics; exposure; mechanisms; metals.

Figure 1

Model illustrating CdCl₂ displacing Zn in TET proteins and histone demethylases. Similarities in physical and chemical properties between Cd and Zn enable them to antagonize each other. Cd has the potential to displace Zn in the Zn finger DNA binding domain of TET protein, which can lead to changes in conformation and activity. Abbreviations: 5-hmC, 5-hydroxymethylcytosine; Cd, cadmium; Cl, chlorine; COOH, carboxylic acid; Cys, cysteine; His, histidine; TET, ten-eleven translocation; Zn, zinc.

Figure 2

Model illustrating NiCl₂ displacing Fe in prolyl hydroxylase domain. By displacing Fe in the PHD, Ni is able to inhibit HIF-prolyl- and asparaginyl-hydroxylases and promote the stabilization of HIFα proteins and HIF-1-dependent transcription. Abbreviations: Cl, chlorine; Fe, iron; HIF −1α, hypoxia-inducible factor 1α; His, histidine; IKKβ, nuclear factor kappa-B kinase subunit β inhibitor; M-MITF, microphthalmia-associated transcription factor type M; Ni, nickel; PHD, prolyl hydroxylase domain protein; TCA, tricarboxylic acid; TET, ten-eleven translocation; VEGF, vascular endothelial growth factor.

Figure 3

Model illustrating NiCl₂ displacing Fe in 2-oxoglutarate-dependent oxygenases. Ni can displace Fe from its active site of Fe-2-oxoglutarate-dependent deoxygenases, which consists of two histidines and a carboxylate acid facial triad. Upon Fe displacement, Ni ions are able to coordinate with the same ligands as Fe, except that Fe is pentacoordinated, allowing for oxygen to bind, whereas Ni is hexacoordinated, resulting in an inactive enzyme. Abbreviations: Cl, chlorine; Fe, iron; Glu, glutamic acid; His, histidine; Ni, nickel.