Journal of Neuro-Oncology

, Volume 130, Issue 1, pp 69–77 | Cite as

Altered tryptophan metabolism in human meningioma

  • Noble Kumar Talari
  • Manas Panigrahi
  • Sailaja Madigubba
  • Sundaram Challa
  • Prakash Babu Phanithi
Laboratory Investigation


Meningiomas are the neoplasms that arise from the arachnoid cells of the meninges. It was reported that cancer cells escape from immune system through the metabolism of an aromatic essential amino acid tryptophan (TRP) via Kynurenine (KYN) pathway. However, the role of TRP metabolites such as, 5-Hydroxy tryptophan (5-HTP), 5-Hydroxy tryptamine (5-HT), N-acetyl serotonin (NAS), Melatonin (MEL), KYN, N-acetyl tryptamine, 5-Hydroxy indole acetic acid (5-HIAA) and 5-Methoxy indole acetic acid is not yet evaluated in human meningioma. Therefore, in the current study we have evaluated the levels of TRP and its metabolites in the progression of human meningioma using tumor biopsy samples and autopsy control meninges with Reverse Phase-HPLC. We here report that TRP metabolism favors towards KYN pathway in human meningioma and it could be due to increased indoleamine 2,3-dioxygenase 2 levels as we found its m-RNA levels to be up regulated in human meningioma. We observed significant increase in KYN and 5HIAA levels and significant decrease in TRP, 5-HTP, 5-HT, NAS and MEL levels in meningioma compared to control meninges. Since TRP metabolites regulate inducible nitric oxide synthase (INOS) gene expression and thereby nitric oxide (NO) production, we have also evaluated the INOS and NO levels. The INOS and NO levels were up regulated in human meningioma. The present data corroborates with existing data on TRP metabolism in tumor progression and may serve to target TRP metabolism as a therapeutic intervention.


Tryptophan Kynurenine Serotonin IDO Meningioma 



This work was supported by grants from the CSIR, ICMR, DST, DBT and UPE. Department of Science and Technology [SB/EMEQ-257/2013, dt. 12 July 2013], Department of Biotechnology [BT/PR13111/MED/29/149/2009, dt. 24 June 2010] and University with Potential for Excellence—Phase II [UH/UGC/UPE-2/Interface Studies/Research Projects/B1.4] New Delhi, Govt. of India. The authors wish to acknowledge help of Dr. Janaki, Kurnool Medical College, Andhra Pradesh, India, for providing autopsy meninges for our study.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest.


  1. 1.
    Marosi C, Hassler M, Roessler K, Reni M, Sant M, Mazza E, Vecht C (2008) Meningioma. Crit Rev Oncol Hematol 67:153–171. doi: 10.1016/j.critrevonc.2008.01.010 CrossRefPubMedGoogle Scholar
  2. 2.
    Mefford IN, Barchas JD (1980) Determination of tryptophan and metabolites in rat brain and pineal tissue by reversed-phase high-performance liquid chromatography with electrochemical detection. J Chromatogr 181:187–193CrossRefPubMedGoogle Scholar
  3. 3.
    Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC (2007) Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indole amine 2,3-dioxygenase inhibitory compound d-1-methyl-tryptophan. Cancer Res 67:7082–7087CrossRefPubMedGoogle Scholar
  4. 4.
    Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197–203. doi: 10.1038/nature10491 CrossRefPubMedGoogle Scholar
  5. 5.
    Lyon DE, Walter JM, Starkweather AR, Schubert CM, McCain NL (2011) Tryptophan degradation in women with breast cancer: a pilot study. BMC Res Notes 4:156. doi: 10.1186/1756-0500-4-156 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    de Jong RA, Nijman HW, Boezen HM, Volmer M, Ten Hoor KA, Krijnen J, van der Zee AG, Hollema H, Kema IP (2011) Serum tryptophan and kynurenine concentrations as parameters for indoleamine 2,3-dioxygenase activity in patients with endometrial, ovarian, and vulvar cancer. Int J Gynecol Cancer 21:1320–1327. doi: 10.1097/IGC.0b013e31822017fb PubMedGoogle Scholar
  7. 7.
    Ferns DM, Kema IP, Buist MR, Nijman HW, Kenter GG, Jordanova ES (2015) Indoleamine-2,3-dioxygenase (IDO) metabolic activity is detrimental for cervical cancer patient survival. Oncoimmunology 4:e981457 (eCollection)CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Sucher R, Kurz K, Weiss G, Margreiter R, Fuchs D, Brandacher G (2010) IDO-mediated tryptophan degradation in the pathogenesis of malignant tumor disease. Int J Tryptophan Res 3:113–120PubMedPubMedCentralGoogle Scholar
  9. 9.
    Prendergast GC (2011) Cancer: why tumours eat tryptophan. Nature 478:192–194. doi: 10.1038/478192a CrossRefPubMedGoogle Scholar
  10. 10.
    Sarrouilhe D, Clarhaut J, Defamie N, Mesnil M (2015) Serotonin and cancer: what is the link? Curr Mol Med 15:62–77. doi: 10.2174/1566524015666150114113411 CrossRefPubMedGoogle Scholar
  11. 11.
    Seuwen K, Pouysségur J (1990) Serotonin as a growth factor. Biochem Pharmacol 39:985–990CrossRefPubMedGoogle Scholar
  12. 12.
    Siddiqui EJ, Thompson CS, Mikhailidis DP, Mumtaz FH (2005) The role of serotonin in tumour growth (review). Oncol Rep 14:1593–1597PubMedGoogle Scholar
  13. 13.
    Muskiet FA, Stratingh MC, Stob GJ, Wolthers BG (1981) Simultaneous determination of the four major catecholamine metabolites and estimation of a serotonin metabolite in urine by capillary gas chromatography of their tert-butyldimethylsilyl derivatives. Clin Chem 27:223–227PubMedGoogle Scholar
  14. 14.
    Carrillo-Vico A, Lardone PJ, Alvarez-Sánchez N, Rodríguez-Rodríguez A, Guerrero JM (2013) Melatonin: buffering the immune system. Int J Mol Sci 14:8638–8683. doi: 10.3390/ijms14048638 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Melillo G, Cox GW, Biragyn A, Sheffler LA, Varesio L (1994) Regulation of nitric-oxide synthase mRNA expression by interferon-gamma and picolinic acid. J Biol Chem 269:8128–8133PubMedGoogle Scholar
  16. 16.
    Dong WG, Mei Q, Yu JP, Xu JM, Xiang L, Xu Y (2003) Effects of melatonin on the expression of iNOS and COX-2 in rat models of colitis. World J Gastroenterol 9:1307–1311CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Mayo JC, Sainz RM, Tan DX, Hardeland R, Leon J, Rodriguez C, Reiter RJ (2005) Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages. J Neuroimmunol 165:139–149CrossRefPubMedGoogle Scholar
  18. 18.
    Esposito E, Iacono A, Muia C et al (2008) Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells. J Pineal Res 44:78–87PubMedGoogle Scholar
  19. 19.
    Mazzoni A, Bronte V, Visintin A, Spitzer JH, Apolloni E, Serafini P, Zanovello P, Segal DM (2002) Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol 168:689–695CrossRefPubMedGoogle Scholar
  20. 20.
    Grady RK Jr, Caliguri A, Mefford IN (1984) Day/night differences in pineal indoles in the adult pigeon (Columba livia). Comp Biochem Physiol C 78:141–143. doi: 10.1016/0742-8413(84)90061-6 CrossRefPubMedGoogle Scholar
  21. 21.
    Zhao J, Chen H, Ni P, Xu B, Luo X, Zhan Y, Gao P, Zhu D (2011) Simultaneous determination of urinary tryptophan, tryptophan-related metabolites and creatinine by high performance liquid chromatography with ultraviolet and fluorimetric detection. J Chromatogr B Analyt Technol Biomed Life Sci 879:2720–2725. doi: 10.1016/j.jchromb.2011.07.035 CrossRefPubMedGoogle Scholar
  22. 22.
    Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254CrossRefPubMedGoogle Scholar
  23. 23.
    Bryan NS, Grisham MB (2007) Methods to detect nitric oxide and its metabolites in biological samples. Free Radic Biol Med 43:645–657CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Zitron IM, Kamson DO, Kiousis S, Juhász C, Mittal S (2013) In vivo metabolism of tryptophan in meningiomas is mediated by indoleamine 2,3-dioxygenase 1. Cancer Biol Ther 14:333–339. doi: 10.4161/cbt.23624 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bosnyák E, Kamson DO, Guastella AR, Varadarajan K, Robinette NL, Kupsky WJ, Muzik O, Michelhaugh SK, Mittal S, Juhász C (2015) Molecular imaging correlates of tryptophan metabolism via the kynurenine pathway in human meningiomas. Neuro Oncol 17:1284–1292. doi: 10.1093/neuonc/nov098 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Huang A, Fuchs D, Widner B, Glover C, Henderson DC, Allen-Mersh TG (2003) Tryptophan and quality of life in colorectal cancer. Adv Exp Med Biol 527:353–358. doi: 10.1258/jrsm.95.10.526-b CrossRefPubMedGoogle Scholar
  27. 27.
    Sakurai K, Fujisaki S, Nagashima S, Maeda T, Tomita R, Suzuki S, Hara Y, Enomoto K, Amano S (2013) Indoleamine 2,3-dioxygenase activity for breast cancer patients with recurrence 5 or more years after surgery. Gan To Kagaku Ryoho 40:1590–1592PubMedGoogle Scholar
  28. 28.
    Lo BK, Jalili RB, Zloty D, Ghahary A, Cowan B, Dutz JP, Carr N, Shapiro J, McElwee KJ (2011) CXCR3 ligands promote expression of functional indoleamine 2,3-dioxygenase in basal cell carcinoma keratinocytes. Br J Dermatol 165:1030–1036. doi: 10.1111/j.1365-2133.2011.10489.x CrossRefPubMedGoogle Scholar
  29. 29.
    Witkiewicz A, Williams TK, Cozzitorto J, Durkan B, Showalter SL, Yeo CJ, Brody JR (2008) Expression of indole amine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. J Am Coll Surg 206:849–854. doi: 10.1016/j.jamcollsurg.2007.12.014 (discussion 854–6)CrossRefPubMedGoogle Scholar
  30. 30.
    Witkiewicz AK, Costantino CL, Metz R, Muller AJ, Prendergast GC, Yeo CJ, Brody JR (2009) Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target. J Am Coll Surg 208:781–787. doi: 10.1016/j.jamcollsurg.2008.12.018 (discussion 787–9)CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (1998) Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281:1191–1193. doi: 10.1126/science.281.5380.1191 CrossRefPubMedGoogle Scholar
  32. 32.
    Mellor AL, Baban B, Chandler P, Marshall B, Jhaver K, Hansen A, Koni PA, Iwashima M, Munn DH (2003) Cutting edge: induced indoleamine 2,3 dioxygenase expression in dendritic cell subsets suppresses T cell clonal expansion. J Immunol 171(4):1652–1655. doi: 10.4049/jimmunol CrossRefPubMedGoogle Scholar
  33. 33.
    Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 11:312–319. doi: 10.1038/nm1196 CrossRefPubMedGoogle Scholar
  34. 34.
    Chugani DC, Muzik O (2000) Alpha[C-11] methyl-l-tryptophan PET maps brain serotonin synthesis and kynurenine pathway metabolism. J Cereb Blood Flow Metab 20:2–9. doi: 10.1097/00004647-200001000-00002 CrossRefPubMedGoogle Scholar
  35. 35.
    Mokhtari M, Rezaei A, Ghasemi A (2015) Determination of urinary 5-hydroxyindoleacetic acid as a metabolomics in gastric cancer. J Gastrointest Cancer 46:138–142. doi: 10.1007/s12029-015-9700-9 CrossRefPubMedGoogle Scholar
  36. 36.
    Jardim-Perassi BV, Arbab AS, Ferreira LC, Borin TF, Varma NR, Iskander AS, Shankar A, Ali MM, de Campos Zuccari DA (2014) Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PLoS One 9:e85311. doi: 10.1371/journal.pone.0085311 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Blask DE, Hill SM, Dauchy RT, Xiang S, Yuan L, Duplessis T, Mao L, Dauchy E, Sauer LA (2011) Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night. J Pineal Res 51:259–269. doi: 10.1111/j.1600-079X.2011.00888.x CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Mediavilla MD, Sanchez-Barcelo EJ, Tan DX, Manchester L, Reiter RJ (2010) Basic mechanisms involved in the anti-cancer effects of melatonin. Curr Med Chem 17:4462–4481. doi: 10.2174/092986710794183015 CrossRefPubMedGoogle Scholar
  39. 39.
    Pandi-Perumal SR, Srinivasan V, Maestroni GJ, Cardinali DP, Poeggeler B, Hardeland R (2006) Melatonin: nature’s most versatile biological signal? FEBS J 273:2813–2838. doi: 10.1111/j.1742-4658.2006.05322.x CrossRefPubMedGoogle Scholar
  40. 40.
    Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR (2011) Melatonin a pleiotropic, orchestrating regulator molecule. Prog Neurobiol 93:350–384. doi: 10.1016/j.pneurobio.2010.12.004 CrossRefPubMedGoogle Scholar
  41. 41.
    Galano A, Tan DX, Reiter RJ (2011) Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res 51:1–16. doi: 10.1111/j.1600-079X.2011.00916.x CrossRefPubMedGoogle Scholar
  42. 42.
    Klotz T, Bloch W, Volberg C, Engelmann U, Addicks K (1998) Selective expression of inducible nitric oxide synthase in human prostate carcinoma. Cancer 82:1897–1903CrossRefPubMedGoogle Scholar
  43. 43.
    Vakkala M, Kahlos K, Lakari E, Pääkkö P, Kinnula V, Soini Y (2000) Inducible nitric oxide synthase expression, apoptosis, and angiogenesis in in situ and invasive breast carcinomas. Clin Cancer Res 6:2408–2416PubMedGoogle Scholar
  44. 44.
    Kojima M, Morisaki T, Tsukahara Y, Uchiyama A, Matsunari Y, Mibu R, Tanaka M (1999) Nitric oxide synthase expression and nitric oxide production in human colon carcinoma tissue. J Surg Oncol 70:222–229CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Noble Kumar Talari
    • 1
  • Manas Panigrahi
    • 2
  • Sailaja Madigubba
    • 2
  • Sundaram Challa
    • 3
  • Prakash Babu Phanithi
    • 1
  1. 1.Laboratory of Neurochemistry, Department of Biotechnology and Bioinformatics, School of Life SciencesUniversity of HyderabadHyderabadIndia
  2. 2.Department of NeurosurgeryKIMSHyderabadIndia
  3. 3.Department of PathologyNIMSHyderabadIndia

Personalised recommendations