IDDF2022-ABS-0024 Transferrin receptor-mediated iron uptake is essential for colon tumorigenesis

Abstract

<h3>Background</h3> Transferrin receptor (TFRC) is the major mediator for iron entry into a cell. Under excessive iron conditions, it is expected that TFRC will be downregulated to reduce iron uptake and toxicity. However, the mechanism whereby TFRC expression is maintained at high levels in iron-enriched cancer cells and the contribution of TFRC to cancer development are enigmatic. <h3>Methods</h3> The regulation and function of TFRC-mediated iron uptake in colon samples were tested in mouse models with colon-specific TFRC disruption and colon-derived cell lines. Transcriptome analysis of patient-derived tumor colonoids was performed to identify molecular targets of iron. <h3>Results</h3> Our work shows TFRC is induced by adenomatous polyposis coli (Apc) gene loss-driven β-catenin activation in colorectal cancer, whereas TFRC-mediated intratumoral iron accumulation potentiates β-catenin signaling by directly enhancing the activity of tankyrase. Disruption of TFRC led to a reduction of colonic iron levels and iron-dependent tankyrase activity, which caused stabilization of Axin2 and subsequent repression of the β-catenin/c-Myc/E2F1/DNA polymerase delta1 (POLD1) axis. POLD1 knockdown, iron chelation and TFRC disruption increased DNA replication stress, DNA damage response, apoptosis and reduced colon tumor growth. Importantly, a combination of iron chelators and DNA damaging agents synergistically induced DNA damage response and reducing colon tumor cell growth. <h3>Conclusions</h3> TFRC-mediated iron import is at the center of a novel feed-forward loop that facilitates colonic epithelial cell survival. This discovery may provide novel strategies for colorectal cancer therapy.