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 Cancer therapy • Proliferation • Cell cycle • GPR35 • AhR Abbreviations 3-HAA 3-Hydroxyanthranilic acid AFMID Kynurenine formamidase (arylformamidase) AhR Aryl hydrocarbon receptor alpha7 nAChR α-7 nicotinic acetylcholine receptor BCRP Breast cancer resistance protein BMSCs Bone marrow stromal cells BRAF B-Raf proto-oncogene, serine/threonine kinase ERK Extracellular signal-regulated kinases GPR35 G protein-coupled receptor 35 HAAO 3-Hydroxyanthranilate 3,4-dioxygenase hOAT Human organic anion transporter IDO Indoleamine 2,3-dioxygenase KAT Kynurenine aminotransferase KMO Kynurenine 3-monooxygenase KRAS KRAS proto-oncogene KYN Kynurenine KYNA Kynurenic acid KYNU Kynureninase MAPK Mitogen-activated protein kinase MDS Myelodysplastic syndrome MGUS Monoclonal gammopathy of undetermined significance MM Multiple myeloma MRP Multidrug resistance protein NMDA N-Methyl-d-aspartate NSCLC Non-small cell lung carcinoma PI3K/Akt Phosphoinositide 3-kinase/protein kinase B PIK3CA Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha PTEN Phosphatase and tensin homolog QPRT Quinolinate phosphoribosyl transferase QUIN Quinolinic acid RCC Renal cell carcinoma SCC Squamous cell carcinoma TDO Tryptophan 2,3-dioxygenase TP53 Tumour protein p53 Cellular and Molecular Life Sciences

Metabolite Sensing GPCRs: Promising Therapeutic Targets for Cancer Treatment?

“…Several studies report alterations in the concentration of KYNA and the expression of GPR35 in different cancers. Increased levels of KYNA have been detected in colon carcinoma, oral squamous cell carcinoma, non-small cell lung carcinoma and multiple myeloma, whereas a reduced concentration of this metabolite was observed in renal cell carcinoma and primary cervical cancer [122]. In parallel, and in comparison to paired normal tissues, the expression of GPR35 was reduced in prostate, testicular and thyroid tumors; increased in stomach, pancreatic, colon and non-small-cell lung cancer, and unaltered in breast and ovarian cancer [122].…”

“…Increased levels of KYNA have been detected in colon carcinoma, oral squamous cell carcinoma, non-small cell lung carcinoma and multiple myeloma, whereas a reduced concentration of this metabolite was observed in renal cell carcinoma and primary cervical cancer [122]. In parallel, and in comparison to paired normal tissues, the expression of GPR35 was reduced in prostate, testicular and thyroid tumors; increased in stomach, pancreatic, colon and non-small-cell lung cancer, and unaltered in breast and ovarian cancer [122]. Functionally, GPR35 signaling pathway via ERK kinase has been involved in several cellular processes such as proliferation, cell survival and even metastasis [123], and overexpression of GPR35 seems to confer drug resistance in non-small-cell lung cancer through β-arrestin-2/Akt signaling [124].…”

Improved Production of Kynurenic Acid by Yarrowia lipolytica in Media Containing Different Honeys

“…This compound is synthesized in the reaction of kynurenine transamination, which is catalyzed by kynurenine aminotransferases (KATs). KYNA exhibits pro-healthy properties, due to its antioxidant, anti-inflammatory and anticonvulsant action [7][8][9]. It was also reported that KYNA can have protective properties on the human brain [9] and an inhibitory effect on the proliferation of colon cancer cells (i.e., adenocarcinoma HT-29 cells) [8].…”

Tryptophan Derivatives by Saccharomyces cerevisiae EC1118: Evaluation, Optimization, and Production in a Soybean-Based Medium

“…It is an antioxidant and neuroprotective compound [ 10 ]; in particular, altered KYNA levels may suggest an inflammatory response, as shown in Alzheimer’s disease patients [ 11 ]. KYNA reduces the heart rate and glaucoma in mice and it has a role in carcinogenesis and cancer therapy [ 12 , 13 , 14 ].…”