Background and aims: Transferrin 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.
Methods: The 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.
Results: Our 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.
Conclusion: Together, 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.
Support or Funding Information
This research was supported in part by the National Institutes of Health (P20 GM130422), a Research Scholar Grant from the American Cancer Society (RSG-18-050-01-NEC), a Shared Resources Pilot Project Award, a Research Program Support Pilot Project Award and a Matching Support Pilot Project Award from University of New Mexico (UNM) comprehensive cancer center (P30CA118100).
This research was supported in part by the National Institutes of Health (P20 GM130422), alt;bgt; lt;/bgt;Research Scholar Grant from the American Cancer Society (RSG-18-050-01-NEC), a Shared Resources Pilot Project Award, a Research Program Support Pilot Project Award and a Matching Support Pilot Project Award from University of New Mexico (UNM) comprehensive cancer center (P30CA118100).
