# Profiling iron-regulated metabolic reprogramming for nucleotide biosynthesis in colon tumors

> **NIH NIH P20** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2020 · $265,125

## Abstract

Colorectal cancer (CRC) is the third leading cause of cancer-related death in US. Understanding the
mechanisms of CRC development is essential to improve treatment. Increased tissue iron in both mice and
humans is associated with increased colon tumorigenesis. However, the precise mechanisms for how iron
contributes to colon carcinogenesis are still unclear. The metabolic differences between normal and cancer
cells are being interrogated to uncover potential new therapeutic approaches. Many tumor cells exhibit
increased glucose consumption, glutamine metabolism and nucleotide synthesis. This proposal will test the
central hypothesis that iron-driven cellular metabolic reprograming promotes DNA synthesis and colon
tumorigenesis. This hypothesis is based on: 1) iron supplement increases, whereas chelation of iron by
deferoxamine (DFO) inhibits the growth and cell proliferation of patient-derived CRC colonoids; 2) treating mice
with high-iron diet increases, while low-iron diet decreases colon tumor multiplicity, incidence and progression;
3) metabolomics analysis reveals that excess iron impacts glucose-stimulated nucleotide synthesis by
promoting hypoxia-independent “Warburg-like effect” and fueling pentose phosphate pathway in colonoids; 4)
iron restriction by DFO leads to glutamine accumulation and reduction of metabolites in nucleotide biosynthesis
pathways in colonoids. Based on these observations, the proposal will test the following three Specific Aims: 1)
Define the mechanism by which excess iron affects glucose-stimulated DNA biosynthesis in CRC; 2) Study the
impact of iron restriction on glutamine-dependent nucleotide synthesis in CRC; 3) Characterize the role of a
DNA polymerase in iron-regulated nucleotide metabolism and CRC. We will utilize highly clinic-relevant CRC
patient-derived colonoid culture, metabolomics analysis, and various animal models. Accomplishing the above
Aims will provide precise molecular mechanisms for how tumor cells are adapted to iron signal to synthesize
nucleotides for facilitating tumor proliferation. These studies will fill our knowledge gap of how iron regulates
CRC growth and progression.

## Key facts

- **NIH application ID:** 9854032
- **Project number:** 1P20GM130422-01A1
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Xiang Xue
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $265,125
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854032

## Citation

> US National Institutes of Health, RePORTER application 9854032, Profiling iron-regulated metabolic reprogramming for nucleotide biosynthesis in colon tumors (1P20GM130422-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9854032. Licensed CC0.

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