Tryptophan 2,3-Dioxygenase-2 in Uterine Leiomyoma: Dysregulation by MED12 Mutation Status

Abstract

Uterine leiomyomas (fibroids) are common benign tumors in women. The tryptophan metabolism through the kynurenine pathway plays important roles in tumorigenesis in general. Leiomyomas expressing mutated mediator complex subunit 12 (mut-MED12) were reported to contain significantly decreased tryptophan levels; the underlying mechanism and the role of the tryptophan metabolism-kynurenine pathway in leiomyoma tumorigenesis, however, remain unknown. We here assessed the expression and regulation of the key enzymes that metabolize tryptophan. Among these, the tissue mRNA levels of tryptophan 2,3-dioxygenase (TDO2), the rate limiting enzyme of tryptophan metabolism through the kynurenine pathway, was 36-fold higher in mut-MED12 compared to adjacent myometrium (P < 0.0001), and 14-fold higher compared to wild type (wt)-MED12 leiomyoma (P < 0.05). The mRNA levels of other tryptophan metabolizing enzymes, IDO1 and IDO2, were low and not significantly different, suggesting that TDO2 is the key enzyme responsible for reduced tryptophan levels in mut-MED12 leiomyoma. R5020 and medroxyprogesterone acetate (MPA), two progesterone agonists, regulated TDO2 gene expression in primary myometrial and leiomyoma cells expressing wt-MED12; however, this effect was absent or blunted in leiomyoma cells expressing G44D mut-MED12. These data suggest that MED12 mutation may alter progesterone-mediated TDO2 expression in leiomyoma, leading to lower levels of tryptophan in mut-MED12 leiomyoma. This highlights that fibroids can vary widely in their response to progesterone as a result of mutation status and provides some insight for understanding the effect of tryptophan-kynurenine pathway on leiomyoma tumorigenesis and identifying targeted interventions for fibroids based on their distinct molecular signatures.

Synthesis of smart carriers based on tryptophan-functionalized magnetic nanoparticles and its application in 5-fluorouracil delivery

“…that C t is the calculated 5-FU concentration in the release profile in time t. V 0 is the total volume of the release media, V ′ is the volume of the deleted sample at particular time intervals, and M t is the initial amount of 5-FU. A similar study was done for pH 5.5 [24,25].…”

“…They are overexpressed in cancer cells. So, this particular interaction as a basis for designing a diagnostic or treatment agent based on MNP can be targeted [23][24][25][26][27][28]. Therefore, TRP is also really crucial in the biochemical, pharmaceutical, and detecting fields, as it is a precursor molecule of some neurotransmitters, hormones, and other relevant biomolecules [22,29], and can act as a suitable TA in DDS.…”

Mono-(2-ethyl-5-hydroxyhexyl) phthalate promotes uterine leiomyoma cell survival through tryptophan-kynurenine-AHR pathway activation

“…Together, these findings strongly suggest that MEHHP activates the AHR pathway and supports LM cell survival at least partially via promoting cellular tryptophan uptake and kynurenine production. In addition, recent studies have revealed that LM tissue exhibited higher TDO2, SLC7A5, SLC7A8, and CYP1B1 gene expression, and higher kynurenine levels compared with MM tissue ( 33 , 34 , 58 ). The AHR pathway in fibroid tissue is activated and leads to higher CYP1B1 expression ( SI Appendix , Fig.…”

“…Studies have shown that phthalates can affect tryptophan metabolism ( 28 , 29 ) and activation of the AHR pathway ( 30 , 31 ), both of which play important roles in regulating cell proliferation, cell cycle, apoptosis, differentiation, metabolism, and tumorigenesis ( 32 ). Recently, we and others reported the involvement of dysregulated tryptophan metabolism in the pathogenesis of LM; however, the mechanisms involved remain to be elucidated ( 33 , 34 ). In this study, we investigated the effects of phthalates on LM cell function, testing the hypothesis that MEHHP (the major metabolite of DEHP) supports LM cell survival through the promotion of tryptophan metabolism and activation of the AHR pathway.…”

A View on Uterine Leiomyoma Genesis through the Prism of Genetic, Epigenetic and Cellular Heterogeneity

“…Other signalling pathways—MAPK, AKT and IGF (insulin-like growth factor) —mediate the action of oestrogen and progesterone in MED12-ULs. Anomalous MED12 protein interacts with the progesterone receptor more efficiently, driving the progesterone-dependent expression of potential carcinogens in MED12-ULs (in particular, this has been shown for the receptor activator of nuclear factor kappa-Β ligand ( RANKL ) and tryptophan 2,3-dioxygenase ( TDO2 ) genes) [ 119 , 120 ]. Gene expression in MED12-ULs is additionally affected by epigenetic abnormalities including post-translation modifications of histones, enhancer architecture and DNA methylation [ 111 , 121 ].…”