Abstract
Cancer cells preferentially accumulate iron (Fe) relative to non-malignant cells; however, the underlying rationale remains elusive. Iron–sulfur (Fe–S) clusters are critical cofactors that aid in a wide variety of cellular functions (e.g., DNA metabolism and electron transport). In this article, we theorize that a differential need for Fe–S biogenesis in tumor versus non-malignant cells underlies the Fe-dependent cell growth demand of cancer cells to promote cell division and survival by promoting genomic stability via Fe–S containing DNA metabolic enzymes. In this review, we outline the complex Fe–S biogenesis process and its potential upregulation in cancer. We also discuss three therapeutic strategies to target Fe–S biogenesis: (i) redox manipulation, (ii) Fe chelation, and (iii) Fe mimicry.
Highlights
There is growing evidence that cancer cells preferentially take up and sequester iron (Fe) relative to non-malignant cells, and it has recently been hypothesized that Fe is a central connection between the genetic and metabolic theories of cancer [1]
Heme synthesis may be regulated by Fe–S biogenesis as the terminal enzyme of the heme synthesis pathway, ferrochelatase (FECH), which contains a [2Fe-2S] cluster that is required for its functioning [13,14,15,16]
MMS19 depletion in HeLa cells resulted in decreased enzymatic activity of the Fe–S protein dihydropyridine dehydrogenase (DPYD) and strongly decreased levels of the POLD1 subunit of DNA polymerase δ [92]
Summary
There is growing evidence that cancer cells preferentially take up and sequester iron (Fe) relative to non-malignant cells, and it has recently been hypothesized that Fe is a central connection between the genetic and metabolic theories of cancer [1]. Cancer cells can limit iron export by producing hepcidin to promote ferroportin (Fpn-1) degradation [5]. RIP in cancer cells, the percentage change between malignant and non-malignant cells is minimal [10] This suggests that most of the intracellular iron is used for functional purposes. Heme synthesis may be regulated by Fe–S biogenesis as the terminal enzyme of the heme synthesis pathway, ferrochelatase (FECH), which contains a [2Fe-2S] cluster that is required for its functioning [13,14,15,16]. Enzymes in cancer progression, the role of iron trafficking and the formation of these tional cofactors are often overlooked. In this manuscript, we summarize the complex Fe–.
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