Involvement of Kynurenine Pathway in Hepatocellular Carcinoma

Krishnamurthy, Shivani; Gilot, David; Ahn, Seong Beom; Lam, Vincent K.; Shin, Joo‐Shik; Guillemin, Gilles J.; Heng, Benjamin

doi:10.3390/cancers13205180

Cited by 13 publications

(17 citation statements)

References 137 publications

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“…Tryptophan and its metabolites including kynurenine and serotonin play critical roles in various cellular growths. 17 In this study the serum levels of tryptophan and serotonin decreased more in HCC patients than in CHB patients. Furthermore, along with the severity of the Child-Pugh class, MELD score, and compensated stage, the serum serotonin level decreased significantly in patients with HCC.…”

Section: Discussionmentioning

confidence: 48%

Serum Amino Acid Profiles Predict the Development of Hepatocellular Carcinoma in Patients with Chronic HBV Infection

Zheng

Yang

et al. 2022

ACS Omega

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Background: The study aimed to find out the alterations in serum amino acid (AA) profiles and to detect their relationship with carcinoma formation. Methods: Targeted metabolomics based on ultraperformance liquid chromatography triple quadrupole mass spectrometry to quantitatively analyze serum AA levels in 136 hepatitis B (CHB) patients and 93 hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. Results: It was shown that decreased serum levels of leucine, lysine, threonine, tryptophan, valine, serotonin, and taurine were observed in more HCC patients than CHB patients, but the serum phenylalanine level was increased. Serum valine and serotonin were lower in Class C than Class A and Class B in HCC patients. Accompanied with the higher score of Model for End-Stage Liver Disease, serum phenylalanine was increased not only in CHB patients but also in HCC patients. The serum level of phenylalanine increased in the decompensated stage more than in the compensated stage, while serum leucine and serotonin significantly decreased. Serum serotonin still had significant differences between CHB and HCC both in the HBV desoxyribonucleic acid (HBV-DNA) negative group and in the HBV-DNA positive group. Furthermore, it was shown that the tryptophan ratio, branched-chain amino acids (BCAA)/aromatic amino acids ratio, BCAAs/tyrosine ratio, Fischer’s ratio, and serotonin-to-tryptophan ratio significantly decreased, while the tyrosine ratio and the kynurenine-to-tryptophan ratio increased in HCC patients more than those in CHB. Conclusions: A distinct metabolite signature of some specific serum amino acids was found between CHB and HCC patients, which may help predict the development of HCC at an early stage.

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Section: Discussionmentioning

confidence: 48%

Serum Amino Acid Profiles Predict the Development of Hepatocellular Carcinoma in Patients with Chronic HBV Infection

Zheng

Yang

et al. 2022

ACS Omega

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“…Under normal physiological conditions, Trp is degraded by two main enzymes—indoleamine 2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO)—to produce a variety of metabolites, including kynurenine (Kyn) [ 4 ]. The degradation of Trp into Kyn has the potential to stimulate tumor growth, as well as influence the immune system by limiting T lymphocyte proliferation and promoting T-cell differentiation [ 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepaRG Tumor Cells

Oweira

Lahdou

Mehrle

et al. 2022

JCM

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There are two main enzymes that convert tryptophan (Trp) to kynurenine (Kyn): tryptophan-2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). Kyn accumulation can promote immunosuppression in certain cancers. In this study, we investigated Trp degradation to Kyn by IDO and TDO in primary human hepatocytes (PHH) and tumoral HepG2 cells. To quantify Trp-degradation and Kyn-accumulation, using reversed-phase high-pressure liquid chromatography, the levels of Trp and Kyn were determined in the culture media of PHH and HepG2 cells. The role of IDO in Trp metabolism was investigated by activating IDO with IFN-γ and inhibiting IDO with 1-methyl-tryptophan (1-DL-MT). The role of TDO was investigated using one of two TDO inhibitors: 680C91 or LM10. Real-time PCR was used to measure TDO and IDO expression. Trp was degraded in both PHH and HepG2 cells, but degradation was higher in PHH cells. However, Kyn accumulation was higher in the supernatants of HepG2 cells. Stimulating IDO with IFN-γ did not significantly affect Trp degradation and Kyn accumulation, even though it strongly upregulated IDO expression. Inhibiting IDO with 1-DL-MT also had no effect on Trp degradation. In contrast, inhibiting TDO with 680C91 or LM10 significantly reduced Trp degradation. The expression of TDO but not of IDO correlated positively with Kyn accumulation in the HepG2 cell culture media. Furthermore, TDO degraded L-Trp but not D-Trp in HepG2 cells. Kyn is the main metabolite of Trp degradation by TDO in HepG2 cells. The accumulation of Kyn in HepG2 cells could be a key mechanism for tumor immune resistance. Two TDO inhibitors, 680C91 and LM10, could be useful in immunotherapy for liver cancers.

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“…The following supporting information can be downloaded at: . References [ 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 , …”

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An Emerging Cross-Species Marker for Organismal Health: Tryptophan-Kynurenine Pathway

Jamshed

Debnath

Jamshed

et al. 2022

IJMS

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Tryptophan (TRP) is an essential dietary amino acid that, unless otherwise committed to protein synthesis, undergoes metabolism via the Tryptophan-Kynurenine (TRP-KYN) pathway in vertebrate organisms. TRP and its metabolites have key roles in diverse physiological processes including cell growth and maintenance, immunity, disease states and the coordination of adaptive responses to environmental and dietary cues. Changes in TRP metabolism can alter the availability of TRP for protein and serotonin biosynthesis as well as alter levels of the immune-active KYN pathway metabolites. There is now considerable evidence which has shown that the TRP-KYN pathway can be influenced by various stressors including glucocorticoids (marker of chronic stress), infection, inflammation and oxidative stress, and environmental toxicants. While there is little known regarding the role of TRP metabolism following exposure to environmental contaminants, there is evidence of linkages between chemically induced metabolic perturbations and altered TRP enzymes and KYN metabolites. Moreover, the TRP-KYN pathway is conserved across vertebrate species and can be influenced by exposure to xenobiotics, therefore, understanding how this pathway is regulated may have broader implications for environmental and wildlife toxicology. The goal of this narrative review is to (1) identify key pathways affecting Trp-Kyn metabolism in vertebrates and (2) highlight consequences of altered tryptophan metabolism in mammals, birds, amphibians, and fish. We discuss current literature available across species, highlight gaps in the current state of knowledge, and further postulate that the kynurenine to tryptophan ratio can be used as a novel biomarker for assessing organismal and, more broadly, ecosystem health.

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Involvement of Kynurenine Pathway in Hepatocellular Carcinoma

Cited by 13 publications

References 137 publications

Serum Amino Acid Profiles Predict the Development of Hepatocellular Carcinoma in Patients with Chronic HBV Infection

Serum Amino Acid Profiles Predict the Development of Hepatocellular Carcinoma in Patients with Chronic HBV Infection

Kynurenine Is the Main Metabolite of Tryptophan Degradation by Tryptophan 2,3-Dioxygenase in HepaRG Tumor Cells

An Emerging Cross-Species Marker for Organismal Health: Tryptophan-Kynurenine Pathway

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