Tryptophan Metabolism and Cancer Progression


  • Kenneth K. Wu Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan and Institute of Biotechnology, National Tsing-Hua University, Hsinchu, Taiwan



Tryptophan metabolites, cancer progression, melatonin, 5-methoxytryptophan, kynurenine.


Abstract: Intracellular tryptophan (Trp) is catabolized to a large repertoire of metabolites via two major pathways: indoleamine and tryptophan 2, 3-dioxygenases (IDO/TDO) and Trp hydroxylase (TPH) pathways. The catabolites possess diverse biological activities and carry out various physiological functions. Several catabolites such as kynurenine (Kyn) and serotonin promote while melatonin and 5-methoxytryptophan (5-MTP) suppress cancer growth and metastasis. Cancer cell-derived Kyn enhances cancer growth and evasion of immunosurveillance by interacting with cancer cell and immune cell membrane aryl hydrocarbon receptors (AHR), respectively. Serotonin exerts its tumor-promoting activities through type 1 and type 2 serotonin receptors. 5-MTP and melatonin suppress cancer growth and metastasis by common mechanisms, i.e., inhibition of p300 histone acetyltransferase (HAT) and NF-κB activation, and suppression of cyclooxygenase-2 and cytokine transcription. Both metabolites block p38 MAPK signaling pathway. Human cancer tissues express increased levels of IDO, TDO and kynurenine monooxygenase (KMO) which are correlated with reduced patient survival. In summary, cancer Trp metabolism regulates cancer growth and metastasis by complex mechanisms. 5-MTP and melatonin provide valuable lead to develop new drugs for chemo-prevention and adjuvant therapy of cancer.


Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 1999; 189(9): 1363-72. DOI:

Terness P, Bauer TM, R¶se L, Dufter C, Watzlik A, Simon H, et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 2002; 196(4): 447-57. DOI:

Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998; 281(5380): 1191-3. DOI:

Schmidt SK, M¼ller A, Heseler K, Woite C, Spekker K, MacKenzie CR, et al. Antimicrobial and immunoregulatory properties of human tryptophan 2,3-dioxygenase. Eur J Immunol 2009; 39(10): 2755-64. DOI:

Chon SY, Hassanain HH, Gupta SL. Cooperative role of interferon regulatory factor 1 and p91 (STAT1) response elements in interferon-gamma-inducible expression of human indoleamine 2,3-dioxygenase gene. J Biol Chem 1996; 271(29): 17247-52. DOI:

Kanai M, Funakoshi H, Takahashi H, Hayakawa T, Mizuno S, Matsumoto K, et al. Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice. Mol Brain 2009; 2:8. DOI:

Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health. Science 2017; 357(6349): eaaf9794. DOI:

Lovenberg W, Jequier E, Sjoerdsma A. Tryptophan hydroxylation: measurement in pineal gland, brainstem, and carcinoid tumor. Science 1967; 155(3759): 217-9. DOI:

Walther DJ, Peter JU, Bashammakh S, H¶rtnagl H, Voits M, Fink H, et al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 2003; 299(5603): 76. DOI:

Christenson JG, Dairman W, Udenfriend S. On the identity of DOPA decarboxylase and 5-hydroxytryptophan decarboxylase (immunological titration-aromatic L-amino acid decarboxylase-serotonin-dopamine-norepinephrine). Proc Natl Acad Sci U S A 1972; 69(2): 343-7. DOI:

Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med 2009; 60: 355-66. DOI:

El-Merahbi R, L¶ffler M, Mayer A, Sumara G. The roles of peripheral serotonin in metabolic homeostasis. FEBS Lett 2015; 589(15): 1728-34. DOI:

Axelrod J, Weissbach H. Enzymatic O-methylation of N-acetylserotonin to melatonin. Science 1960; 131(3409): 1312. DOI:

Klein DC. Arylalkylamine N-acetyltransferase: "the Timezyme". J Biol Chem 2007; 282(7): 4233-7. DOI:

Hardeland R, Pandi-Perumal SR, Cardinali DP. Melatonin. Int J Biochem Cell Biol 2006; 38(3): 313-6. DOI:

Cheng HH, Kuo CC, Yan JL, Chen HL, Lin WC, Wang KH, et al. Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan. Proc Natl Acad Sci U S A 2012; 109(33): 13231-6. DOI:

Chen HL, Yuan CY, Cheng HH, Chang TC, Huang SK, Kuo CC, et al. Restoration of hydroxyindole O-methyltransferase levels in human cancer cells induces a tryptophan-metabolic switch and attenuates cancer progression. J Biol Chem 2018; 293(28): 11131-11142. DOI:

Wang YF, Hsu YJ, Wu HF, Lee GL, Yang YS, Wu JY, et al. Endothelium-Derived 5-Methoxytryptophan Is a Circulating Anti-Inflammatory Molecule That Blocks Systemic Inflammation. Circ Res 2016; 119(2): 222-36. DOI:

Th©ate I, van Baren N, Pilotte L, Moulin P, Larrieu P, Renauld JC, et al. Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues. Cancer Immunol Res 2015; 3(2): 161-72. DOI:

Abdel-Magid AF. Targeting the Inhibition of Tryptophan 2,3-Dioxygenase (TDO-2) for Cancer Treatment. ACS Med Chem Lett 2016; 8(1): 11-13. DOI:

Du L, Xing Z, Tao B, Li T, Yang D, Li W, et al. Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn-AhR-AQP4 signaling pathway. Signal Transduct Target Ther 2020; 5(1): 10. DOI:

Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 2011; 478(7368): 197-203. DOI:

Murray IA, Patterson AD, Perdew GH. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 2014; 14(12): 801-14. DOI:

Munn DH, Mellor AL. IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance. Trends Immunol 2016; 37(3): 193-207. DOI:

Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med 2002; 196(4): 459-68. DOI:

Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ 2002; 9(10): 1069-77.

Orabona C, Puccetti P, Vacca C, Bicciato S, Luchini A, Fallarino F, et al. Toward the identification of a tolerogenic signature in IDO-competent dendritic cells. Blood 2006; 107(7): 2846-54. DOI:

Hill M, Tanguy-Royer S, Royer P, Chauveau C, Asghar K, Tesson L, et al. IDO expands human CD4+CD25high regulatory T cells by promoting maturation of LPS-treated dendritic cells. Eur J Immunol 2007; 37(11): 3054-62. DOI:

Xue P, Fu J, Zhou Y. The Aryl Hydrocarbon Receptor and Tumor Immunity. Front Immunol 2018; 9: 286. DOI:

Nocito A, Dahm F, Jochum W, Jang JH, Georgiev P, Bader M, et al. Serotonin regulates macrophage-mediated angiogenesis in a mouse model of colon cancer allografts. Cancer Res 2008; 68(13): 5152-8. DOI:

Alpini G, Invernizzi P, Gaudio E, Venter J, Kopriva S, Bernuzzi F, et al. Serotonin metabolism is dysregulated in cholangiocarcinoma, which has implications for tumor growth. Cancer Res 2008; 68(22): 9184-93. DOI:

Soll C, Jang JH, Riener MO, Moritz W, Wild PJ, Graf R, et al. Serotonin promotes tumor growth in human hepatocellular cancer. Hepatology 2010; 51(4): 1244-54. DOI:

Leoncikas V, Wu H, Ward LT, Kierzek AM, Plant NJ. Generation of 2,000 breast cancer metabolic landscapes reveals a poor prognosis group with active serotonin production. Sci Rep 2016; 6: 19771. DOI:

Sarrouilhe D, Clarhaut J, Defamie N, Mesnil M. Serotonin and cancer: what is the link? Curr Mol Med 2015; 15(1): 62-77. DOI:

Ichinose H, Sumi-Ichinose C, Ohye T, Hagino Y, Fujita K, Nagatsu T. Tissue-specific alternative splicing of the first exon generates two types of mRNAs in human aromatic L-amino acid decarboxylase. Biochemistry 1992; 31(46): 11546-50. DOI:

Albert VR, Lee MR, Bolden AH, Wurzburger RJ, Aguanno A. Distinct promoters direct neuronal and nonneuronal expression of rat aromatic L-amino acid decarboxylase. Proc Natl Acad Sci U S A 1992; 89(24): 12053-7. DOI:

O'Malley KL, Harmon S, Moffat M, Uhland-Smith A, Wong S. The human aromatic L-amino acid decarboxylase gene can be alternatively spliced to generate unique protein isoforms. J Neurochem 1995; 65(6): 2409-16. DOI:

Vachtenheim J, Novotn¡ H. Expression of the aromatic L-amino acid decarboxylase mRNA in human tumour cell lines of neuroendocrine and neuroectodermal origin. Eur J Cancer 1997; 33(14): 2411-7. DOI:

Bepler G, Jaques G, Koehler A, Gropp C, Havemann K. Markers and characteristics of human SCLC cell lines. Neuroendocrine markers, classical tumor markers, and chromosomal characteristics of permanent human small cell lung cancer cell lines. J Cancer Res Clin Oncol 1987; 113(3): 253-9. DOI:

Kontos CK, Papadopoulos IN, Fragoulis EG, Scorilas A. Quantitative expression analysis and prognostic significance of L-DOPA decarboxylase in colorectal adenocarcinoma. Br J Cancer 2010; 102(9): 1384-90. DOI:

Koutalellis G, Stravodimos K, Avgeris M, Mavridis K, Scorilas A, Lazaris A, et al. L-dopa decarboxylase (DDC) gene expression is related to outcome in patients with prostate cancer. BJU Int 2012; 110(6 Pt B): E267-73. DOI:

Gilroy DW, Saunders MA, Sansores-Garcia L, Matijevic-Aleksic N, Wu KK. Cell cycle-dependent expression of cyclooxygenase-2 in human fibroblasts. FASEB J 2001; 15(2): 288-90. DOI:

Deng WG, Saunders M, Gilroy D, He XZ, Yeh H, Zhu Y, et al. Purification and characterization of a cyclooxygenase-2 and angiogenesis suppressing factor produced by human fibroblasts. FASEB J 2002; 16(10): 1286-8. DOI:

Cheng HH, Wang KH, Chu LY, Chang TC, Kuo CC, Wu KK. Quiescent and proliferative fibroblasts exhibit differential p300 HAT activation through control of 5-methoxytryptophan production. PLoS One 2014; 9(2): e88507. DOI:

Cheng HH, Chu LY, Chiang LY, Chen HL, Kuo CC, Wu KK. Inhibition of cancer cell epithelial mesenchymal transition by normal fibroblasts via production of 5-methoxytryptophan. Oncotarget 2016; 7(21): 31243-56. DOI:

Chu LY, Wang YF, Cheng HH, Kuo CC, Wu KK. Endothelium-Derived 5-Methoxytryptophan Protects Endothelial Barrier Function by Blocking p38 MAPK Activation. PLoS One 2016; 11(3): e0152166. DOI:

Ho YC, Wu ML, Su CH, Chen CH, Ho HH, Lee GL, et al. A Novel Protective Function of 5-Methoxytryptophan in Vascular Injury. Sci Rep 2016; 6: 25374. DOI:

Flaberg E, Markasz L, Petranyi G, Stuber G, Dicso F, Alchihabi N, et al. High-throughput live-cell imaging reveals differential inhibition of tumor cell proliferation by human fibroblasts. Int J Cancer 2011; 128(12): 2793-802. DOI:

Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 1999; 59(19): 5002-11.

Rodriguez IR, Mazuruk K, Schoen TJ, Chader GJ. Structural analysis of the human hydroxyindole-O-methyltransferase gene. Presence of two distinct promoters. J Biol Chem 1994; 269(50): 31969-77. DOI:

Donohue SJ, Roseboom PH, Illnerova H, Weller JL, Klein DC. Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA. DNA Cell Biol 1993; 12(8): 715-27. DOI:

Botros HG, Legrand P, Pagan C, Bondet V, Weber P, Ben-Abdallah M, et al. Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway. J Pineal Res 2013; 54(1): 46-57. DOI:

Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, et al. Melatonin for the prevention and treatment of cancer. Oncotarget 2017; 8(24): 39896-39921. DOI:

Reiter RJ. Mechanisms of cancer inhibition by melatonin. J Pineal Res 2004; 37(3): 213-4. DOI:

Reiter RJ, Rosales-Corral SA, Tan DX, Acuna-Castroviejo D, Qin L, Yang SF, et al. Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis. Int J Mol Sci 2017; 18(4): 843. DOI:

Hill SM, Belancio VP, Dauchy RT, Xiang S, Brimer S, Mao L, et al. Melatonin: an inhibitor of breast cancer. Endocr Relat Cancer 2015; 22(3): R183-204. DOI:

Mart­n V, Herrera F, Carrera-Gonzalez P, Garc­a-Santos G, Antol­n I, Rodriguez-Blanco J, et al. Intracellular signaling pathways involved in the cell growth inhibition of glioma cells by melatonin. Cancer Res 2006; 66(2): 1081-8. DOI:

Galano A, Reiter RJ. Melatonin and its metabolites vs oxidative stress: From individual actions to collective protection. J Pineal Res 2018; 65(1): e12514. DOI:

Chang TC, Hsu MF, Shih CY, Wu KK. 5-methoxytryptophan protects MSCs from stress induced premature senescence by upregulating FoxO3a and mTOR. Sci Rep 2017; 7(1): 11133. DOI:

Wang J, Xiao X, Zhang Y, Shi D, Chen W, Fu L, et al. Simultaneous modulation of COX-2, p300, Akt, and Apaf-1 signaling by melatonin to inhibit proliferation and induce apoptosis in breast cancer cells. J Pineal Res 2012; 53(1): 77-90. DOI:

Deng WG, Zhu Y, Wu KK. Up-regulation of p300 binding and p50 acetylation in tumor necrosis factor-alpha-induced cyclooxygenase-2 promoter activation. J Biol Chem 2003; 278(7): 4770-7. DOI:

Deng WG, Zhu Y, Wu KK. Role of p300 and PCAF in regulating cyclooxygenase-2 promoter activation by inflammatory mediators. Blood 2004; 103(6): 2135-42. DOI:

Mao L, Yuan L, Slakey LM, Jones FE, Burow ME, Hill SM. Inhibition of breast cancer cell invasion by melatonin is mediated through regulation of the p38 mitogen-activated protein kinase signaling pathway. Breast Cancer Res 2010; 12(6): R107. DOI:

Huether G. The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates. Experientia 1993; 49(8): 665-70. DOI:

Renzi A, DeMorrow S, Onori P, Carpino G, Mancinelli R, Meng F, et al. Modulation of the biliary expression of arylalkylamine N-acetyltransferase alters the autocrine proliferative responses of cholangiocytes in rats. Hepatology 2013; 57(3): 1130-41. DOI:

Han Y, Demorrow S, Invernizzi P, Jing Q, Glaser S, Renzi A, et al. Melatonin exerts by an autocrine loop antiproliferative effects in cholangiocarcinoma: its synthesis is reduced favoring cholangiocarcinoma growth. Am J Physiol Gastrointest Liver Physiol 2011; 301(4): G623-33. DOI:

Pan K, Wang H, Chen MS, Zhang HK, Weng DS, Zhou J, et al. Expression and prognosis role of indoleamine 2,3-dioxygenase in hepatocellular carcinoma. J Cancer Res Clin Oncol 2008; 134(11): 1247-53. DOI:

Yu CP, Fu SF, Chen X, Ye J, Ye Y, Kong LD, et al. The Clinicopathological and Prognostic Significance of IDO1 Expression in Human Solid Tumors: Evidence from a Systematic Review and Meta-Analysis. Cell Physiol Biochem 2018; 49(1): 134-143. DOI:

Wang Y, Yao R, Zhang L, Xie X, Chen R, Ren Z. IDO and intra-tumoral neutrophils were independent prognostic factors for overall survival for hepatocellular carcinoma. J Clin Lab Anal 2019; 33(5): e22872. DOI:

Liu Q, Zhai J, Kong X, Wang X, Wang Z, Fang Y, et al. Comprehensive Analysis of the Expression and Prognosis for TDO2 in Breast Cancer. Mol Ther Oncolytics 2020; 17: 153-168. DOI:

Li S, Li L, Wu J, Song F, Qin Z, Hou L, et al. TDO Promotes Hepatocellular Carcinoma Progression. Onco Targets Ther 2020; 13: 5845-5855. DOI:

Huang TT, Tseng LM, Chen JL, Chu PY, Lee CH, Huang CT, et al. Kynurenine 3-monooxygenase upregulates pluripotent genes through β-catenin and promotes triple-negative breast cancer progression. EBioMedicine 2020; 54: 102717. DOI:

Jin H, Zhang Y, You H, Tao X, Wang C, Jin G, et al. Prognostic significance of kynurenine 3-monooxygenase and effects on proliferation, migration, and invasion of human hepatocellular carcinoma. Sci Rep 2015; 5: 10466. DOI:

Huang JY, Butler LM, Midttun ˜, Ulvik A, Wang R, Jin A, et al. A prospective evaluation of serum kynurenine metabolites and risk of pancreatic cancer. PLoS One 2018; 13(5): e0196465. DOI:

Karayama M, Masuda J, Mori K, Yasui H, Hozumi H, Suzuki Y, et al. Comprehensive assessment of multiple tryptophan metabolites as potential biomarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer. Clin Transl Oncol 2020. DOI:

Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ 2002; 9(10): 1069-77. DOI:



2021-09-16 — Updated on 2021-09-16

How to Cite

K. Wu, K. (2021). Tryptophan Metabolism and Cancer Progression . Journal of Analytical Oncology, 10, 1–11.