Iron-Sulfur Cluster Biogenesis as a Critical Target in Cancer

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.

Keywords: cancer therapy; carcinogenesis; iron metabolism; iron–sulfur cluster biogenesis.

Figure 1

Fe–S biogenesis is theorized to represent a fundamental difference between cancer and non-malignant cells. Cancer cells frequently exhibit a phenotype characterized by preferential Fe uptake and downregulation of Fe export. The underlying mechanism is unclear, but we hypothesize that this may be related to increased cancer cell needs for Fe–S biogenesis to produce cytosolic and nuclear Fe–S proteins necessary for cancer cell survival.

Figure 2

Factors involved in [2Fe-2S] cluster formation and transfer by the scaffold protein, ISCU. (1). Initial cluster formation occurs on ISCU with sulfur donation occurring by the cysteine desulfurases, NFS1/IscS (in prokaryotes). Frataxin binds at the interface of ISCU and NFS1 to allow for access to the PLP site to allow for persulfide transfer to ISCU. FXN facilitates this process. LYRM4 and ACP1 enhanceS complex stability. (2). Following completion of the [2Fe-2S] cluster on ISCU, an ISCU[2Fe-2S]-HSC20-HSPA9 complex is formed that facilitates the ATPase activity of HSPA9 allowing for [2Fe-2S] transfer to GLRX5. GLRX5 can rapidly transfer the [2Fe-2S] cluster to target proteins.

Figure 3

Step 3: Factors involved in mitochondrial [4Fe-4S] cluster formation. (A) Following [2Fe-2S] cluster formation and transfer to GLRX5, 2 molecules of holo-GLRX5 can bind with ISCA1/2. The formation of a heterodimer of [2Fe-2S]-ISCA1/2 allows for IBA57 and FDX2 dependent [4Fe-4S] assembly. (B) Following [2Fe-2S] cluster formation on ISCU, holo-ISCU and holo-ISCA1 can bind at the C-terminal domain of NFU1 to allow for [4Fe-4S] cluster formation on NFU1 in an FDX2-dependent manner. (C) Following the transfer of a [2Fe-2S] cluster from ISCU to GLXR5, a holo-GLXR5-BOLA3 complex can donate a [2Fe-2S] cluster to NFU1 for [4Fe-4S] cluster assembly. This is reduction-dependent and likely dependent on FDX2.

Figure 4

Formation and trafficking of [4Fe-4S] clusters to extramitochondrial target proteins occur via the cytosolic iron–sulfur assembly (CIA) pathway. The transmembrane protein, ABCB7, transfers the appropriate Fe and S for de novo extramitochondrial cluster synthesis, thought to be in the form of a glutathione-coordinated [2Fe-2S] cluster ([2Fe-2S](SG)₄). On the outer mitochondrial membrane, CISD1/2 are thought to be able to transfer a reduced [2Fe-2S] cluster to the CIAPIN-NDOR1 complex, facilitated by GLRX3. This [2Fe-2S] cluster may be transferred for de novo [4Fe-4S] synthesis on the NUBP1/2 scaffolding complex facilitated by CIAO3. The [4Fe-4S] cluster is transferred to the CIAO1–CIAO2B–MMS19 complex, where MMS19 can directly interact with cytosolic and nuclear target apo-proteins for cluster insertion.

Figure 5

Therapeutic strategies to target the Fe–S biogenesis pathway. Current strategies to target the Fe–S biogenesis pathway to induce cancer cell killing include Fe chelation to prevent intracellular trafficking, iron mimicry in the form of Ga³⁺ to function as a Fe antagonist and impair the Fe–S biogenesis process, and pro-oxidants (e.g., ionizing radiation) to perturb Fe–S containing proteins.

Figure 6

ROS-mediated oxidation of aconitase-like [4Fe-4S] clusters. ROS (H₂O₂, O₂^•−, ONOO⁻, HO^•, HO₂^•) can oxidize the aconitase [4Fe-4S]²⁺ cluster leading to the release of a non-cys bound Fe atom.

Figure 7

Structure of different Fe-chelator complexes. Hexadentate Fe–chelators (e.g., desferrioxamine) bind Fe with 1:1 stoichiometry. Tridentate chelators (e.g.,) bind Fe with 2:1 stoichiometry. Bidentate chelators (e.g.,) bind Fe with 3:1 stoichiometry.

Figure 8

Valence electron configuration of Fe³⁺ and Ga³⁺. Energy level diagram of the d-orbital shell of Fe³⁺ and Ga³⁺ when bound in an octahedral coordination environment (6 ligands). The d-orbital of Fe³⁺ is partially filled with 5 unpaired electrons (S = 5/2) while Ga³⁺ has a d-orbital with 10 paired electrons (S = 10). The completed d-orbital of Ga³⁺ prevents redox cycling (154).