Tryptophan Catabolism is Dysregulated in Leiomyomas

Overview

Journal Fertil Steril

Specialty Reproductive Medicine

Date 2021 Jun 12

PMID 34116832

Citations 16

Authors

Tsai-Der Chuang

Derek Quintanilla

Drake Boos

Omid Khorram

Affiliations

Soon will be listed here.

Abstract

Objective: To determine the expression and functional roles of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) in leiomyoma.

Design: Experimental study.

Setting: Academic research laboratory.

Patient(s): Women undergoing hysterectomy for leiomyoma.

Intervention(s): Blockade of IDO1 and TDO2.

Main Outcome Measure(s): Expression of IDO1 and TDO2 in leiomyoma and the effects of their inhibitors on the extracellular matrix.

Result(s): Leiomyoma expressed significantly higher levels of IDO1 and TDO2 messenger ribonucleic acid (mRNA; 60.3%, 35/58 pairs and 98.3%, 57/58 pairs, respectively) and protein (54%, 27/50 pairs and 92%, 46/50 pairs, respectively) as well as the enzyme activity marker kynurenine (78.3%, 36/46 pairs for IDO1/TDO2) compared with levels in matched myometrium. The expression of TDO2 but not IDO1 mRNA was significantly higher in fibroids from African American compared with that in Caucasian and Hispanic patients. The TDO2 but not the IDO1 protein and mRNA levels were more abundant in fibroids bearing the MED12 mutation compared with results in wild-type leiomyomas. Treatment of leiomyoma smooth muscle cell and myometrial smooth muscle cell spheroids with the TDO2 inhibitor 680C91 but not the IDO1 inhibitor epacadostat significantly repressed cell proliferation and the expression of collagen type I (COL1A1) and type III (COL3A1) in a dose-dependent manner; these effects were more pronounced in leiomyoma smooth muscle cells compared with myometrial smooth muscle cell spheroids.

Conclusion(s): These results underscore the physiological significance of the tryptophan degradation pathway in the pathogenesis of leiomyomas and the potential utility of anti-TDO2 drugs for treatment of leiomyomas.

Citing Articles

Therapeutic targeting of the tryptophan-kynurenine-aryl hydrocarbon receptor pathway with apigenin in MED12-mutant leiomyoma cells.

Iizuka T, Zuberi A, Wei H, Coon V J, Anton M, Buyukcelebi K Cancer Gene Ther. 2025; .

PMID: 40025195 DOI: 10.1038/s41417-025-00881-0.

In Vivo Effects of Bay 11-7082 on Fibroid Growth and Gene Expression: A Preclinical Study.

Chuang T, Ton N, Rysling S, Khorram O Cells. 2024; 13(13.

PMID: 38994944 PMC: 11240737. DOI: 10.3390/cells13131091.

Characterization of m6A Modifiers and RNA Modifications in Uterine Fibroids.

George J, Cancino R, Griffin Miller J, Qiu F, Lin Q, Rowley M Endocrinology. 2024; 165(8).

PMID: 38946397 PMC: 11222979. DOI: 10.1210/endocr/bqae074.

Altered extracellular matrix-related pathways accelerate the transition from normal to prefibroid myometrium in Black women.

Bariani M, Grimm S, Coarfa C, Velez Edwards D, Yang Q, Walker C Am J Obstet Gynecol. 2024; 231(3):324.e1-324.e12.

PMID: 38825029 PMC: 11344675. DOI: 10.1016/j.ajog.2024.05.048.

Targeting the long non-coding RNA MIAT for the treatment of fibroids in an animal model.

Chuang T, Ton N, Manrique N, Rysling S, Khorram O Clin Sci (Lond). 2024; 138(12):699-709.

PMID: 38817011 PMC: 11166562. DOI: 10.1042/CS20240190.

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