# The kynurenine-AHR pathway in biomass production - Revision - 2

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $42,312

## Abstract

PROJECT SUMMARY
 Increased uptake and synthesis of macromolecules is essential to sustain the demands of hyperproliferative
cancer cells. Therefore, developing approaches to limit biomass production specifically in tumors could have
profound implications for cancer treatment. While seminal studies have shown that the universal oncogene
MYC promotes protein synthesis in cancer cells, there is still a gap in our understanding of how MYC molecularly
controls translation during oncogenic transformation. We found that the transcription factor aryl hydrocarbon
receptor (AHR) and its ligand kynurenine, a byproduct of the amino acid tryptophan, are induced by MYC in
colon cancer cells. Our preliminary results indicate that AHR is necessary for the expression of genes involved
in ribosomal biogenesis and protein synthesis in proliferating cells. Our hypothesis is that AHR senses and
responds to tryptophan-derived kynurenine by translocating into the nucleus and inducing the transcription of
genes that mediate ribosome biogenesis and translation in colon cancer cells. Aim 1 will directly test the role of
AHR in protein synthesis in colon cancer cells, using genetic silencing in isogenic lines of human colonic
epithelial cells and of mouse organoids progressed to colon cancer. Aim 2 will establish the contribution of
kynurenine to AHR-regulated protein synthesis and cell proliferation by examining the requirement for
kynurenine for the expression of AHR target genes, protein synthesis, and growth. We will utilize AHR knockout
cells and a competitive inhibitor that prevents the binding of kynurenine to AHR to define AHR-specific functions
regulated by kynurenine. Aim 3 will directly test the importance of tryptophan-metabolizing enzymes in
generating kynurenine and in regulating proliferation of colonic cells. We will determine the effects of knocking
down or knocking out enzymes in the kynurenine pathway to define their requirement for AHR activity, protein
synthesis, and proliferation of colon cancer cells and organoids. This study has the potential to define a direct
physiological role for the kynurenine-AHR pathway in driving increased biomass production and cell proliferation
in colon cancer. Moreover, this study will broaden the understanding of the role of kynurenine as an
oncometabolite. Our findings could become the basis for the development of novel approaches to limit
kynurenine production and AHR activity as a means to treat MYC-dependent tumors.

## Key facts

- **NIH application ID:** 10596385
- **Project number:** 3R01CA245548-03S2
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Maralice Conacci-Sorrell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $42,312
- **Award type:** 3
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10596385

## Citation

> US National Institutes of Health, RePORTER application 10596385, The kynurenine-AHR pathway in biomass production - Revision - 2 (3R01CA245548-03S2). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10596385. Licensed CC0.

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