Tryptophan catabolism is dysregulated in leiomyomas

Area of Science:

• Biochemistry
• Molecular Biology
• Gynecology

Background:

• Leiomyomas (uterine fibroids) are common benign tumors.
• The tryptophan-kynurenine pathway, involving IDO1 and TDO2, plays a role in immune regulation and cell proliferation.
• Understanding the role of IDO1 and TDO2 in leiomyoma pathogenesis is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the expression and functional significance of indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) in human leiomyomas.
• To evaluate the impact of inhibiting IDO1 and TDO2 on leiomyoma cell behavior and extracellular matrix production.

Main Methods:

• Quantitative analysis of IDO1 and TDO2 mRNA and protein expression in leiomyoma and myometrium tissues.
• Measurement of kynurenine, an enzyme activity marker.
• In vitro treatment of leiomyoma and myometrial smooth muscle cell spheroids with IDO1 and TDO2 inhibitors.
• Assessment of cell proliferation and collagen type I and III expression.

Main Results:

• Significantly elevated IDO1 and TDO2 mRNA and protein levels, along with kynurenine, were observed in leiomyomas compared to matched myometrium.
• TDO2 expression correlated with race and MED12 mutation status in leiomyomas.
• The TDO2 inhibitor 680C91, but not the IDO1 inhibitor epacadostat, dose-dependently suppressed leiomyoma cell proliferation and collagen synthesis, with greater effects in leiomyoma cells.

Conclusions:

• The tryptophan degradation pathway, particularly TDO2, is physiologically significant in leiomyoma development.
• Targeting TDO2 with specific inhibitors presents a promising therapeutic strategy for managing leiomyomas.