Iron: An Essential Element of Cancer Metabolism

Abstract

Cancer cells undergo considerable metabolic changes to foster uncontrolled proliferation in a hostile environment characterized by nutrient deprivation, poor vascularization and immune infiltration. While metabolic reprogramming has been recognized as a hallmark of cancer, the role of micronutrients in shaping these adaptations remains scarcely investigated. In particular, the broad electron-transferring abilities of iron make it a versatile cofactor that is involved in a myriad of biochemical reactions vital to cellular homeostasis, including cell respiration and DNA replication. In cancer patients, systemic iron metabolism is commonly altered. Moreover, cancer cells deploy diverse mechanisms to increase iron bioavailability to fuel tumor growth. Although iron itself can readily participate in redox reactions enabling vital processes, its reactivity also gives rise to reactive oxygen species (ROS). Hence, cancer cells further rely on antioxidant mechanisms to withstand such stress. The present review provides an overview of the common alterations of iron metabolism occurring in cancer and the mechanisms through which iron promotes tumor growth.

Keywords: cancer metabolism; iron; iron-sulfur cluster; mitochondria.

Figure 1

Simplified scheme of cellular iron metabolism in cancer cells. Red: upregulation reported in cancer. Blue: downregulation reported in cancer. Cancer cells commonly show increased uptake of iron by transferrin receptor 1 (TfR1). After binding of transferrin-bound iron (Tf-Fe or TBI) on its receptor, the complex is carried to the intracellular space by endocytosis. Coordination of six-transmembrane epithelial antigen of prostate (STEAP) and divalent metal transporter (DMT1) releases free iron in the cytosol. Circulating free, non-transferrin-bound iron (NTBI) can also be imported by ZIP14. Hepcidin (HEPC) secretion by the liver downregulates ferroportin (FPN) levels, consequently causing iron accumulation in the intracellular space. Cancer cells also deploy other iron-acquisition methods, e.g., via heme importers, including HCP1, CD91, and CD193. Heme-responsive gene 1 (HRG1) allows the cytosolic release of heme imported by endocytosis. Moreover, increased ferritinophagy, and hence the degradation of ferritin–iron (FT) complexes by NCOA4, further increases bioavailable iron. Altogether, these mechanisms lead to elevated labile iron pool (LIP). After incorporation in enzymes’ prosthetic moieties or alone as a cofactor by the mitochondria, iron can fuel the TCA cycle and the electron transport chain or be exported to the cytosol and participate in translational process as well as DNA replication or repair.

Figure 2

Crosstalk between oncogenes, signaling pathways, and iron regulators. Red: upregulation reported in cancer. Blue: downregulation reported in cancer. Several oncogenic transcription factors, signaling pathways, and proto-oncogenes directly regulate key players of iron metabolism. Notably, TfR1 upregulation can be caused by activation of HIF1 and MYC overexpression of IRP2, or loss of wild-type p53 [51,155,184,185]. Similarly, ferritin (FT) decrease can result from activation of MYC, IRP2, or p53 mutation [51,155,185]. Such a vicious cycle is sustained as increased LIP promotes CDK, JAK/STAT, PI3K, MAPK/ERK pathways [172], whereas heme can further enhance ERK and MYC and inhibits p53 [181,186,187].