Iron and thiols as two major players in carcinogenesis: friends or foes?

Abstract

Iron is the most abundant metal in the human body and mainly works as a cofactor for proteins such as hemoglobin and various enzymes. No independent life forms on earth can survive without iron. However, excess iron is intimately associated with carcinogenesis by increasing oxidative stress via its catalytic activity to generate hydroxyl radicals. Biomolecules with redox-active sulfhydryl function(s) (thiol compounds) are necessary for the maintenance of mildly reductive cellular environments to counteract oxidative stress, and for the execution of redox reactions for metabolism and detoxification. Involvement of glutathione S-transferase and thioredoxin has long attracted the attention of cancer researchers. Here, I update recent findings on the involvement of iron and thiol compounds during carcinogenesis and in cancer cells. It is now recognized that the cystine/glutamate transporter (antiporter) is intimately associated with ferroptosis, an iron-dependent, non-apoptotic form of cell death, observed in cancer cells, and also with cancer stem cells; the former with transporter blockage but the latter with its stabilization. Excess iron in the presence of oxygen appears the most common known mutagen. Ironically, the persistent activation of antioxidant systems via genetic alterations in Nrf2 and Keap1 also contributes to carcinogenesis. Therefore, it is difficult to conclude the role of iron and thiol compounds as friends or foes, which depends on the quantity/distribution and induction/flexibility, respectively. Avoiding further mutation would be the most helpful strategy for cancer prevention, and myriad of efforts are being made to sort out the weaknesses of cancer cells.

Keywords: Nrf2; cancer stem cell; carcinogenesis; ferroptosis; glutathione; iron; oxidative stress; peroxiredoxins.

Figure 1

Differences between atherosclerosis and carcinogenesis as oxidative stress-induced diseases.

Figure 2

Molecular carcinogenic processes in terms of oxidative stress.

Figure 3

Oxygen as a medium for electron flow and the associated role of catalytic ferrous iron (Fe[II]) toward Fenton reaction. Note that only a small fraction generates hydroxyl radicals (^·OH). Refer to text and Figure 7.

Figure 4

Macroscopic appearance of ferric nitrilotriacetate (Fe-NTA)-induced renal cell carcinoma (interrupted circle; tumor diameter is more than 40 mm). K, normal kidney of the opposite side; L, liver; T, testis.

Figure 5

Molecular mechanism of ferric nitrilotriacetate (Fe-NTA)-induced oxidative damage of renal proximal tubules after a single intraperitoneal injection. This depends on two distinct characteristics of renal proximal tubular lumina: paucity of antioxidattive proteins such as albumin and reductive environment through the presence of L-cysteine with GSH cycles.

Figure 6

Consequences of Fenton reaction in the genome DNA during carcinogenesis. HNE, 4-hydroxy-2-nonenal.

Figure 7

Antagonizing role of iron and thiol compounds. Numerous overlapping mechanisms using thiol compounds exist to decompose hydrogen peroxide to water in order to bypass the generation of hydroxyl radicals. Hydrogen peroxide is now recognized as a signaling molecule whose main regulator is the peroxiredoxin/sulfiredoxin systems, which are at least partially under the control of the Nrf2/Keap1 system. Some cancers hijack Nrf2/Keap1 system with mutation in these genes, which persistently activate antioxidant systems in the cancer cells. Refer to text and Figure 8 for details.

Figure 8

Regulation of Nrf2 transcription machinery through oxidative stress sensor, Keap1, with numerous redox-reactive cysteine residues.

Figure 9

Key role of the cystine/glutamate antiporter in cancer cells. (A) Overexpression of CD44v(8-11) stabilizes the cystine/glutamate antiporter to increase cysteine and glutathione (GSH) in cancer stem cells. (B) Conversely, erastin blocks the cystine/glutamate antiporter, lowers cysteine and finally induces iron-dependent cancer cell death (ferroptosis), which can be blocked with deferoxamine (DFO).