Hyeoncheol Kim, Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM, 87131, USA.
Luke B. Villareal, Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM, 87131, USA.
Zhaoli Liu, Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM, 87131, USA.
Mohammad Haneef, Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM, 87131, USA.
Daniel M. Falcon, Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM, 87131, USA.
David R. Martin, Department of Pathology, University of New Mexico, Albuquerque, NM, 87131, USA.
Ho-Joon Lee, Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
Michael K. Dame, Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, 48109, USA.
Durga Attili, Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Ying Chen, Center for clinical research and translational medicine, Yangpu hospital, Tongji University School of Medicine, Shanghai, 200090, China.
James Varani, Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Jason R. Spence, Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, 48109, USA.
Olga Kovbasnjuk, Division of Gastroenterology and Hepatology, Department of Medicine, the University of New Mexico, Albuquerque, NM, 87131, USA.
Justin A. Colacino, Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA.
Costas A. Lyssiotis, Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
Henry C. Lin, Section of Gastroenterology, Medicine Service, New Mexico VA Health Care System, Albuquerque, NM, 87108, USA.
Yatrik M. Shah, Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA.
Xiang Xue, Department of Biochemistry and Molecular Biology, University of New Mexico, Albuquerque, NM, 87131, USA.

Document Type

Article

Publication Date

4-1-2023

Abstract

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.

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