posted on 2024-10-16, 10:20authored 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>Tracing of TRP demonstrates that inflammatory cytokines enhance TRP catabolism and accumulation of KYN and other downstream catabolites. <b>A,</b> MDA-MB-453 cultured in TRP-depleted media with <sup>13</sup>C<sub>11</sub>-labeled TRP for 8 hours were treated with vehicle or 10 ng/mL IL1β + TNFα for 24 or 48 hours, and cell pellets were lysed and subjected to MS. Labeled intracellular TRP catabolites (heavy, dark blue) or unlabeled (light, light blue) were measured. including (<b>B</b>) TRP, (<b>C</b>) formyl-KYN, (<b>D</b>) KYN, (<b>E</b>) 3-hydroxykynurenine, and (<b>F</b>) kynurenic acid shown as peak area. Biological replicates were conducted in each group, and data are displayed as mean ± SEM by Student <i>t</i> test analysis. *, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001; ****, <i>P</i> < 0.0001.</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.