Kynurenic acid and cancer: facts and controversies

Abstract

Kynurenic acid (KYNA) is an endogenous tryptophan metabolite exerting neuroprotective and anticonvulsant properties in the brain. However, its importance on the periphery is still not fully elucidated. KYNA is produced endogenously in various types of peripheral cells, tissues and by gastrointestinal microbiota. Furthermore, it was found in several products of daily human diet and its absorption in the digestive tract was evidenced. More recent studies were focused on the potential role of KYNA in carcinogenesis and cancer therapy; however, the results were ambiguous and the biological activity of KYNA in these processes has not been unequivocally established. This review aims to summarize the current views on the relationship between KYNA and cancer. The differences in KYNA concentration between physiological conditions and cancer, as well as KYNA production by both normal and cancer cells, will be discussed. The review also describes the effect of KYNA on cancer cell proliferation and the known potential molecular mechanisms of this activity.

Keywords: AhR; Cancer therapy; Cell cycle; GPR35; Proliferation.

Fig. 1

The kynurenine pathway of tryptophan degradation. The selected enzymes of the kynurenine pathway are shown in a simplified scheme. AFMID kynurenine formamidase (arylformamidase), HAAO 3-hydroxyanthranilate 3,4-dioxygenase, IDO indoleamine-2,3-dioxygenase, KATs kynurenine aminotransferases [includes four isoenzymes: KAT I (KYAT1), KAT II (AADAT), KAT III (KYAT3), KAT IV (GOT2)], KMO kynurenine-3-monooxygenase, KYNU kynureninase, QPRT quinolinate phosphoribosyl transferase, TDO tryptophan 2,3-dioxygenase, NAD nicotinamide adenine dinucleotide

Fig. 2

The fate of KYNA in the body—a schematic representation of factors affecting its level. The level of KYNA in the tissues and body fluids depends on its endogenous production, supply and elimination from the body. KYNA is endogenously produced in cells and as a result of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) activity [2, 3, 24] or by direct transformation of kynurenine to KYNA by reactive oxygen species [126]. KYNA is also delivered to the body with food, beverages and herbs [25, 57, 118]. Importantly, intestinal microflora may participate in the formation of the overall amount of KYNA in gastrointestinal tract [23]. KYNA concentration in serum may be also dependent on the efficiency of KYNA excretion from the body with urine. However, it was suggested that KYNA may be excreted with bile as a consequence of the enterohepatic circulation [22]. Our unpublished data showed that KYNA is present in faeces, but its origin (undigested food, intestinal microflora or the way of KYNA excretion from the body) has not been elucidated. Question mark (?) means that there is no direct evidence that KYNA found in faeces comes from blood

Fig. 3

A schematic presentation of selected cellular processes influenced by KYNA. KYNA inhibits phosphorylation of protein kinase B (Akt), extracellular signal-regulated kinase (ERK 1/2), and p38 mitogen-activated protein kinase (p38) [99]. The effect of KYNA on phosphoinositide 3-kinase/protein kinase B PI3K/Akt pathway may lead to disruption of various cellular processes including proliferation, cell cycle, cell survival and migration. Interaction between KYNA and ERK pathway may affect the processes of differentiation, proliferation or apoptosis, whereas interaction between KYNA and p38 pathway may affect the processes of proliferation, cell motility, apoptosis, stress response and inflammation. Moreover, KYNA enhances the protein expression of β-catenin which is involved in adhesion, development, cell survival and proliferation. The potential relationship between AhR (a) and GPR35 (b) receptors and mentioned signalling pathways is presented; however, the specific mechanism of KYNA interactions has not been fully elucidated. a KYNA is an agonist of the aryl hydrocarbon receptor AhR. According to the biological effects of AhR activation, three possible types of interactions may be suggested: via PI3K/Akt pathway, ERK signalling pathway or by activation of the expression of xenobiotic and non-xenobiotic target genes (based on [–129]). b KYNA activates G-protein-coupled receptor 35 (GPR35) which may lead to inhibition of phosphorylation of various signalling proteins, including Akt, ERK, and p38 mitogen-activated protein kinase (p38). Additionally, activation of GPR35 may lead to increase in β-catenin expression (based on [59, 130]). c KYNA enhances the protein expression of cyclin-dependent kinase (CDK) inhibitor p21^Waf1/Cip1 resulting in possible inhibition of cyclin D/CDK4/CDK6, cyclin E/CDK2, cyclin A/CDK2 and cyclin B/CDK1 complexes which may lead to cell cycle arrest and antiproliferative activity [63]

Fig. 4

Data mining on GPR35 gene expression and on mutation frequency of genes composing kynurenine pathway. aGPR35 gene expression profiles across normal tissues and paired tumours and were generated using GEPIA2 [131] based on TCGA [95] and GTEx [96] datasets. Retrieved expression values are provided in transcripts per million (TPM) as normal (green) vs. cancer (red) for every listed tissue. Four types of tumours were identified to display significant downregulation of GPR35 (left side of the panel; marked by ↓). Five different types of tumours showed significant upregulation of GPR35 in comparison to respective normal tissues (right side of the panel; marked by ↑). No significant changes in GPR35 expression in other types of tumours were identified. Two examples of such tumours are given on the top of the panel (=). Statistical analysis: ANOVA (q value cutoff = 0.01;|Log₂FC| cutoff = 1). Red colour intensity on different parts of the depicted human anatomical outline represents the expression level of GPR35 in human cancers. TPM, transcripts per million; ↑, upregulation of GPR35 in cancer vs. normal; ↓, downregulation of GPR35 in cancer vs. normal; (=), no significant changes in GPR35 expression. b Data on the frequency of mutations in genes involved in tryptophan catabolism on the kynurenine pathway were extracted from TCGA [95] database through Genomic Data Commons Data Portal available at https://portal.gdc.cancer.gov. A set of five genes commonly mutated in human cancers were provided for comparison. TP53 tumor protein p53, PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, PTEN phosphatase and tensin homolog, KRAS KRAS proto-oncogene, GTPase, BRAF B-Raf proto-oncogene, serine/threonine kinase, KMO kynurenine 3-monooxygenase, KYNU kynureninase, IDO2 indoleamine 2,3-dioxygenase 2, IDO1 indoleamine 2,3-dioxygenase 1, TDO2 tryptophan 2,3-dioxygenase, AFMID arylformamidase; KYAT3 (KAT III), kynurenine aminotransferase 3, KYAT1 (KAT I) kynurenine aminotransferase 1, AADAT (KAT II) aminoadipate aminotransferase, GOT2 (KAT IV), glutamic-oxaloacetic transaminase 2, HAAO 3-hydroxyanthranilate 3,4-dioxygenase, QPRT quinolinate phosphoribosyltransferase

Fig. 5

Expression pattern of genes coding kynurenine aminotransferases (KAT I–IV) in human tumours with down- and upregulated CDKN1A (p21^Waf1/Cip1). GEPIA2 [131] was queried for tumours displaying significant changes in the expression of CDKN1A, gene encoding for p21^Waf1/Cip1 cyclin-dependent kinase inhibitor. Ovarian serous cystadenocarcinoma and testicular germ cell tumour displayed significant downregulation of CDKN1A in comparison to paired normal tissues (a). On the contrary, pancreatic adenocarcinoma and lymphoid neoplasm diffuse large B-cell lymphoma showed significant upregulation of CDKN1A (b). Expression of genes coding for kynurenine aminotransferases, i.e., KYAT1 (KAT I; c, d), AADAT (KAT II; e, f), KYAT3 (KAT III; g, h) and GOT2 (KAT IV; i, j), was examined in the same set of cancers. Significant downregulation of KYAT1 (c) and AADAT (e), but not of AADAT (g) nor of GOT2 (i), was observed in ovarian serous cystadenocarcinoma and testicular germ cell tumours–tumours displaying CDKN1A (p21^Waf1/Cip1) downregulation. CDKN1A (p21^Waf1/Cip1) upregulation in pancreatic adenocarcinoma was accompanied by an increase in KYAT1 (KAT I; d) and GOT2 (KAT IV; j). Similarly, lymphoid neoplasm diffuse large B-cell lymphoma showed increase in KYAT1 (KAT I, d), KYAT3 (KAT III; h) and GOT2 (KAT IV; j). Differences in the expression levels were analysed by ANOVA. *p < 0.01 and fold-change threshold (|Log₂FC| cutoff) of 1