Targeting Iron Metabolism for Colorectal Cancer Treatment

Abstract

Hypoxia is a key feature of most solid tumors including colorectal cancer (CRC). Hypoxia‐inducible factors (HIFs) are the major transcription factors that respond to hypoxia and are essential for tumor survival and growth. However, the main downstream pathways of HIF‐mediated tumor growth are not clear. We show that HIF‐mediated dysregulation of intratumoral intestinal iron homeostasis through induction of the iron uptake transporter divalent metal transporter 1 (DMT1) and a ferrireductase six‐transmembrane epithelial antigen of prostate 4 (STEAP4) is a major mechanism leading to CRC. Decreasing intratumoral iron by low iron diet or germ‐line Dmt1 knockout inhibits, whereas genetic overexpression of STEAP4 promotes CRC progression. If this is a druggable pathway and could serve as a therapeutic method for CRC is not known. We generated a mouse model with a temporal and conditional disruption of Dmt1 gene in the intestine (VilERT2 Dmt1F/F) by crossing Dmt1F/F mice with Villin‐CreERT2 transgenic mice, carrying a tamoxifen‐inducible Cre. Colorectal tumors were first established in this mouse model by one dose of azoxymethane (AOM) and three cycles of 1.5% dextran sulfate sodium (DSS), and then mice were treated with three daily doses of 100 mg/kg tamoxifen to disrupt Dmt1 in established colorectal tumor epithelium. One month later tumor number, tumor size at 2–3 mm and 3–4 mm, and tumor burden were significantly reduced in VilERT2 Dmt1F/F mice compared to their littermate control (Dmt1F/F). Consistent with the findings in human CRC, the gene expression of Dmt1 was increased in the tumor tissues compared to normal adjacent tissues in littermate control mice, and significantly decreased in both normal and tumor tissues in VilERT2 Dmt1F/F mice. Immunofluorescence staining revealed that cell proliferation, as determined by bromodeoxyuridine (BrdU) and Ki67 staining, was not changed, but cell apoptosis assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and cleaved caspase 3 (cCasp3) staining was increased in colorectal tumor tissues from VilERT2 Dmt1F/F mice compared to control mice. In addition, tumor vascularization and macrophage infiltration were not altered. These results demonstrate that Dmt1 is critical for tumor growth in the AOM‐DSS‐induced mouse colitis‐tumor model, and targeting iron metabolism is a feasible strategy for CRC treatment.Support or Funding InformationX.X. was supported by NIH Grant 1K01DK114390‐01 and a Research Scholar Award from the American Gastroenterological Association. Y.M.S. was supported by NIH Grants CA148828 and DK095201.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.