Minerals and Cancer: Overview of the Possible Diagnostic Value

Abstract

Cancer is the second leading cause of death worldwide and is expected to increase by one-third over the next two decades, in parallel with the growing proportion of the elderly population. Treatment and control of cancer incidence is a global issue. Since there is no clear way to prevent or cure this deadly malignancy, diagnostic, predictive, and prognostic markers for oncological diseases are of great therapeutic value. Minerals and trace elements are important micronutrients for normal physiological function of the body. They are abundant in natural food sources and are regularly included in dietary supplements whereas highly processed industrial food often contains reduced or altered amounts of them. In modern society, the daily intake, storage pools, and homeostasis of these micronutrients are dependent on certain dietary habits and can be thrown out of balance by malignancies. The current work summarizes the data on minerals and trace elements associated with abnormal accumulation or depletion states in tumor patients and discusses their value as potential tumor-associated biomarkers that could be introduced into cancer therapy.

Keywords: biomarkers; calcium; cancer; copper; iodine; iron; minerals; phosphorus; selenium; zinc.

Figure 1

Overview of the involvement of minerals in oncogenesis. Minerals are involved in several and overlapping cellular pathways. Iron is sequestered by ferritin inside the cytoplasm. Iron leaking from the ferritin cages can react with water to form hydroxyl radical, one of the many ROS. Vitamin C promotes the reload of iron inside the ferritin cages. ROS can interact with lipid bilayers, generating more ROS molecules by lipid peroxidation, a process inhibited by iodide. In addition, ROS can directly damage the DNA and proteins, including the DNA-repair enzymes that are activated by ROS-induced damage. Furthermore, ROS activates p53 and NF-κB, altering the cell cycle. Iodide, SOD1, and GPx2 inactivate ROS. For instance, SOD1 removes superoxide radicals by dismutation reaction generating H₂O₂, O₂, and GPx2 by producing two H₂O from auto-reduction. The DNA-repair factors are modulated by the zinc-protein ERp72, which regulates the intake of vitamin D involved in the regulation of transcriptional factors. Cellular intake of vitamin D is also regulated by phosphorus. ERp72 reduces disulfide bonds in nascent proteins in the ER, in association with the calcium-proteins CNX and CRT. Moreover, ERp72 regulates NF-κB, the latter being also modulated by GPx2 and Sep15. GPx2 and Sep15 promote their own expression. A20 and AKT also activate NF-κB, which then reduces the activity of A20 in a negative feedback loop. AKT is modulated by LOX, MEMO1, and IP3, and affects the cell cycle by promoting the expression of CycD1. LOX can alter genetic expression by modifying the histones. Some transcription factors contain zinc, and a transcription regulator is p53, which TR1 modulates. ATOX1 is a zinc-containing protein that can modulate gene expression, particularly that of cyclin D1 and SOD3 (which regulates the oxidative environment outside the cell). Genetic transcription and cell cycle are regulated by ERK, which MEK1 activates after being phosphorylated by the complex Ras/Braf. One of the modulators of Ras is CaM, but also phosphorus can directly boost its activation. Similarly, phosphorus is also part of active IP3 that, aside from its direct modulation of AKT, regulates the release of calcium (effectively a second messenger on its own right) from the ER via the Ca²⁺ channel IP3R. The P-type ATPase SERCA mediates the transport of cytosolic calcium back into the ER. CRT regulates both IP3R and SERCA. Moreover, minerals are involved in DNA replication since they are embedded in several subunits of the DNA replication complex (namely: iron in the helicase, primase, and DNA-polymerase α, the latter two also containing zinc). Iron is present in the first three mitochondrial complexes and CytC, whereas copper is present in complex IV. Thus, minerals are essential to the energetic balance of the cell and its oxidative state. AKT, Ak strain transforming; A20, zinc finger protein A20; ATOX1, antioxidant-1; Braf, rapidly accelerated fibrosarcoma isoform B; CaM, calmodulin; CNX, calnexin; CRT, calreticulin; CycD1, cyclin D1; CytC, cytochrome c; DNA-pol, DNA polymerase; ER, endoplasmic reticulum; Erp72, endoplasmic reticulum resident protein 72; ERK, extracellular signal-regulated kinase; GPx2, glutathione peroxidase 2; IκB, NF-κB inhibitor; IKK, IκB kinase; IP3, inositol 1,4,5-trisphosphate; IP3R, inositol trisphosphate receptor; LOX, lysyl oxidase; MAPK, mitogen-activated protein kinase; MEK1, MAPK/ERK kinase1; MEMO1, mediator of cell motility 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Q, coenzyme Q; Ras, rat sarcoma virus; RNR, ribonucleotide reductase; ROS, reactive oxygen species; Sep15, selenoprotein of 15-kDa; SERCA, sarco-/endoplasmic reticulum calcium ATPase; SOD, superoxide dismutase; TR1, thioredoxin reductase 1.