Transferrin Receptor-Mediated Iron Uptake Promotes Colon Tumorigenesis

Adv Sci (Weinh). 2023 Apr;10(10):e2207693. doi: 10.1002/advs.202207693. Epub 2023 Jan 26.


Transferrin receptor (TFRC) is the major mediator for iron entry into a cell. Under excessive iron conditions, TFRC is expected to be reduced to lower 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. Here the 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 leads to a reduction of colonic iron levels and iron-dependent tankyrase activity, which caused stabilization of axis inhibition protein 2 (AXIN2) and subsequent repression of the β-catenin/c-Myc/E2F Transcription Factor 1/DNA polymerase delta1 (POLD1) axis. POLD1 knockdown, iron chelation, and TFRC disruption increase DNA replication stress, DNA damage response, apoptosis, and reduce colon tumor growth. Importantly, a combination of iron chelators and DNA damaging agents increases DNA damage response and reduces colon tumor cell growth. 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.

Keywords: DNA damage response; TFRC; colon; iron; β-catenin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinogenesis / genetics
  • Cell Transformation, Neoplastic
  • Colonic Neoplasms* / genetics
  • Humans
  • Iron / metabolism
  • Receptors, Transferrin / genetics
  • Receptors, Transferrin / metabolism
  • Tankyrases* / metabolism
  • beta Catenin / metabolism


  • beta Catenin
  • Iron
  • Tankyrases
  • Receptors, Transferrin