Version 2 2025-04-03, 21:47Version 2 2025-04-03, 21:47
Version 1 2024-10-16, 10:20Version 1 2024-10-16, 10:20
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posted on 2025-04-03, 21:47authored byLi-Wei Kuo, Lyndsey S. Crump, Kathleen O’Neill, Michelle M. Williams, Jessica L. Christenson, Nicole S. Spoelstra, Micaela Kalani Roy, Amy Argabright, Julie A. Reisz, Angelo D’Alessandro, Meher P. Boorgula, Andrew Goodspeed, Mike Bickerdike, Benjamin G. Bitler, Jennifer K. Richer
<p>Pharmacologic inhibition of TDO2/IDO1 or <i>TDO2</i> KD reduces the EMT signature. <b>A–C,</b> GSEA was performed to analyze RNA-seq data from BT549 treated with AT-0174 or vehicle (AT-0174 vs. vehicle) for 48 hours, and BT549 with <i>TDO2</i> KD [sh<i>TDO2</i>-82 vs. shSCR and sh<i>TDO2</i>-98 (IDO1 comp) vs. sh<i>TDO2</i>-82], with biological triplicate for each condition. Significant pathways (<i>P</i> adj. < 0.05) with negative (blue) and positive (red) NES for the hallmark of EMT genes are shown. <b>D</b> and <b>E,</b> Heatmaps of the EMT gene subset from RNA-seq data with <i>z</i>-score-transformed CPM. <b>F</b> and <b>G,</b><i>VIM</i> and <i>CDH2</i> mRNA as by qPCR following AT-0174 treatment for 48 hours. Data are displayed as mean ± SD with <i>t</i> test or one-way ANOVA analysis. *, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001; ****, <i>P</i> < 0.0001. <i>CDH2</i>, <i>N</i>-<i>cadherin</i>; CPM, counts per million; NES, normalized enrichment score; <i>VIM</i>, <i>vimentin</i>.</p>
TDO2 is more highly expressed than the nonhomologous TRP-catabolizing enzyme IDO1 in TNBC. We find that TDO2 knockdown can lead to a compensatory increase in IDO1. Therefore, we tested a newly developed TDO2/IDO1 dual inhibitor and found that it decreases TRP catabolism, anchorage-independent survival, and invasive capacity.