Transferrin receptor‐mediated iron uptake is essential for colon tissue homeostasis

Abstract

Background and aimsTransferrin receptor (TFRC) is the major mediator for iron entry into a cell. Under excessive iron conditions, TFRC is expected to be downregulated via the iron regulatory protein and the iron‐responsive element machinery to reduce iron uptake and toxicity. However, the mechanism by which the expression of TFRC is maintained high in iron‐enriched cancer cells and its contribution to cancer development are enigmatic.MethodsThe regulation and function of TFRC‐mediated iron uptake in colon 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.ResultsOur work shows TFRC is induced by adenomatous polyposis coli gene loss‐driven β‐catenin activation in colorectal cancer, whereas TFRC‐mediated intratumoral iron accumulation potentiates β‐catenin signaling via directly enhancing the activity of tankyrase. TFRC‐mediated iron import is at the center of this novel feed‐forward loop to facilitate colonic epithelial cell survival. Mechanistically, 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 b‐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. Strikingly, a combination of iron chelators and DNA damaging agents caused a synergistic effect in inducing DNA damage response and reducing colon tumor cell growth.ConclusionTogether, the TFRC/iron/tankyrase/Axin2/b‐catenin/c‐Myc/E2F1/POLD1 axis is essential for colon homeostasis and may provide potential novel strategies for colorectal cancer therapy.