Noninvasive Serum Metabolomic Profiling Reveals Elevated Kynurenine Pathway’s Metabolites in Humans with Prostate Cancer

Abstract

This study aimed to apply high-resolution metabolomics to detect compounds that may contribute significantly to prostate cancer (PCa) development. The test population's sera for evaluating the metabolic differences consisted of healthy control (n = 96) and PCa (n = 50) groups. PCa patients were further divided into two groups based on whether their PSA level was >4 (n = 25) or <4 (n = 25). Univariate analysis was performed with the false discovery rate (FDR) at q = 0.05 to determine significantly different metabolites. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) clearly distinguished healthy subjects from PCa groups, while no significant difference was observed in PCa patients with PSA level < 4 or > 4. Mummichog, in combination with the KEGG and MetaboAnalyst, showed that tryptophan metabolism along the kynurenine pathway was most significantly enriched, with −log (p) < 0.05. L-Tryptophan, kynurenine, anthranilate, isophenoxazine, glutaryl-CoA, (S)-3-hydroxybutanoyl-CoA, acetoacetyl-CoA, and acetyl-CoA were upregulated in correlation with the PSA level of PCa patients; in contrast, indoxyl, indolelactate, and indole-3-ethanol, involved in the alternative pathway, were downregulated in the PCa patients. Validation and quantification of potential metabolites by MS/MS further confirmed the disruption of tryptophan, kynurenine, and anthranilate, suggesting that the metabolites of this pathway are potential biomarkers in patients with PCa.

Kynurenine Pathway Metabolites as Biomarkers for Amyotrophic Lateral Sclerosis

“…Using these modern techniques, the KP has been investigated as a marker for progression, severity, and prognostic for diseases such as systemic lupus erythematosus (Perl, 2015; Åkesson et al, 2018), cancers (Jin et al, 2015; Zuo et al, 2016; Xie et al, 2017; Huang et al, 2018; Liu et al, 2018; Khan et al, 2019), cardiovascular disease (Sun et al, 2013; Zuo et al, 2016), lung cancer and chronic obstructive pulmonary disease (Chuang et al, 2014; Zinellu et al, 2018), chronic kidney disease and diabetes (Hirayama et al, 2012; Zhao, 2013), acquired immunodeficiency syndrome (AIDS) and HIV-dementia (Fuchs et al, 1990; Heyes et al, 1991; Sardar et al, 2002; Guillemin et al, 2005b; Favre et al, 2010; Lee et al, 2016; Wang et al, 2019), pancreatic cysts (Park et al, 2013), acute myeloid leukemia and lymphomas (Giusti et al, 1996; Finger et al, 2017), vitamin levels (Midttun et al, 2014), tuberculosis (Weiner et al, 2012; Feng et al, 2015), malaria (Medana et al, 2003), irritable bowel syndrome (IBS) (Clarke et al, 2012; Gupta et al, 2012), rheumatoid arthritis (Spiera and Vallarino, 1969; Schroecksnadel et al, 2003), growth deficits (Kosek et al, 2016), obesity (Mangge et al, 2014), and preeclampsia (Nilsen et al, 2012). In the nervous system, the KP has been shown to associate with pathologies such as stroke (Darlington et al, 2007), schizophrenia (Müller and Schwarz, 2006; Kegel et al, 2014; Oxenkrug et al, 2016), Parkinson’s (Ogawa et al, 1992; Widner et al, 2002; Lewitt et al, 2013; Havelund et al, 2017), neuropsychiatric disorders such as depression and stress (Mackay et al, 2009; Gabbay et al, 2010; Olsson et al, 2010; Steiner et al, 2011; Kocki et al, 2012; Erhardt et al, 2013; Comai et al, 2016; Küster et al, 2017; Huang et al, 2018; Kuwano et al, 2018), suicide (Erhardt et al, 2013; Bay-Richter et al, 2015; Brundin et al, 2016), multiple sclerosis (Rejdak et al, 2002; Lim et al, 2017)...…”

Metabolomics Contributions to the Discovery of Prostate Cancer Biomarkers

“…Moreover, additional clinically robust biomarkers able to differentiate between indolent and aggressive PCa are urgently needed. In this context, several metabolomics studies have been carried out to attempt the characterization of a specific PCa metabolic profile, with the ultimate goal of identifying potential metabolic biomarkers that could improve the clinical management of PCa patients [16,17,18,19].…”

Meningeal dendritic cells-astrocytes interactions elevate the kynurenine metabolic pathway to sustain neuropathic pain

“…Noteworthy, there is evidences that 3-Hk and QA synergistically induced neuronal changes and death, which would be occurring in neuropathic pain 76,77 . Our study also advances in conditions, in which pain has a neuropathic component [87][88][89] . Therefore, further studies will be necessary to addresses whether KYNPATH is a common mechanism among different types of neuropathic pain.…”