Redox Regulation in Cancer Cells during Metastasis

Abstract

Metastasis is an inefficient process in which the vast majority of cancer cells are fated to die, partly because they experience oxidative stress. Metastasizing cancer cells migrate through diverse environments that differ dramatically from their tumor of origin, leading to redox imbalances. The rare metastasizing cells that survive undergo reversible metabolic changes that confer oxidative stress resistance. We review the changes in redox regulation that cancer cells undergo during metastasis. By better understanding these mechanisms, it may be possible to develop pro-oxidant therapies that block disease progression by exacerbating oxidative stress in cancer cells. SIGNIFICANCE: Oxidative stress often limits cancer cell survival during metastasis, raising the possibility of inhibiting cancer progression with pro-oxidant therapies. This is the opposite strategy of treating patients with antioxidants, an approach that worsened outcomes in large clinical trials.

Figure 1.

Metabolic pathways that generate NADPH are important sources of reducing equivalents for oxidative stress resistance. A, Glutathione (GSH) and thioredoxin (TRX_red) are redox buffers that are used by antioxidant enzymes such as superoxide dismutase (SOD), peroxiredoxin (PRDX), and glutathione peroxidase 4 (GPX4) to neutralize ROS, including O₂⁻, H₂O₂, and lipid ROS. The reduced forms of GSH and TRX can then be regenerated from the oxidized forms [glutathione disulfide (GSSG); TRX_ox] by glutathione reductase (GR) or thioredoxin reductase (TRXR), which obtain reducing equivalents from NADPH. NADP⁺ is generated de novo from NAD⁺ by NAD kinase (NADK; ref. 167). NADP⁺ is then reduced to NADPH by the pentose phosphate pathway, the folate pathway, malic enzyme (ME1, 2, or 3), glutamate dehydrogenase (GDH1/2), or isocitrate dehydrogenase (IDH1/2; ref. 86). Other abbreviations in this panel include electron transport chain (ETC), glucose-6-phosphate dehydrogenase (G6PD), phosphogluconate dehydrogenase (PGD), dihydrofolate reductase (DHFR), methylenetetrahydrofolate dehydrogenase 1/2 (MTHFD1/2), NADPH oxidase (NOX), superoxide dismutase (SOD), and catalase (CAT). B, Schematic of reactions in which antioxidant enzymes transfer reducing equivalents between NADPH, GSH, and ROS.

Figure 2.

The regulation of ferroptosis. A, Lipid ROS, including lipid peroxides, arise as a result of the oxidation of polyunsaturated fatty acids (PUFA), driven by Fenton reactions in which redox active iron generates hydroxyl radicals (•OH). These PUFAs are present in membrane phospholipids (PL). Cells have multiple antioxidant defenses that oppose the accumulation of lipid ROS including the selenocystine (Se) enzyme, glutathione peroxidase 4 (GPX4), and the reducing agents squalene (100), tetrahydrobiopterin (BH₄; ref. 105), and ubiquinol/α-tocopheral. Abbreviations include transferrin receptor protein 1 (TFR1), acyl-CoA synthetase long-chain family member 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), lysyl oxidase (LOX), six-transmembrane epithelial antigen of prostate 3 (STEAP3), divalent metal transporter 1 (DMT1), ferroptosis suppressor protein 1 (FSP1; refs. 168, 169), dihydrofolate reductase (DHFR), 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), TRNA Isopentenyltransferase 1 (TRIT1), glutathione (GSH), glutathione disulfide (GSSG), farnesyl-diphosphate farnesyltransferase 1 (FDFT1). B, Schematic of reactions in which iron generates hydroxyl radicals (•OH) that react with bis-allylic hydrogens in PUFAs to generate lipid ROS (99). C, Generation of stable lipid alcohols from lipid ROS by GPX4.

Figure 3.

Potential pro-oxidant therapies. It may be possible to inhibit the metastasis or progression of some cancers using pro-oxidant therapies that exacerbate the oxidative stress experienced by cancer cells.