Exercise as a Kynurenine Pathway Modulator in Cancer: Traditional Review

Öz

The overactivation of related enzymes of the kynurenine pathway in cancer and increase of chemical conversion metabolites in blood serum levels provide an immunologically sensitive microenvironment for mutant cells to survive and invade surrounding tissues. In particular, overactivation of indoleamine 2,3-dioxygenase 1 is thought to play a role as a determinant of the pathogenesis and poor disease prognosis in various cancers such as gastrointestinal cancers, gynecological cancers, hematological malignancies, breast cancer, lung cancer, glioma, melanoma, prostate, and pancreatic cancer. Additionally, kynurenic acid has been shown to increase quinolinic acid concentrations in the cerebrospinal fluid, leading to inflammation and leading to depressive symptoms. In this context, research on kynurenine pathway metabolites has gained momentum in explaining tumor formation, prognosis, and side effects due to cancer itself or its treatments. Previous studies have shown that both acute and chronic exercise can cause up/down-regulation of kynurenine pathway enzymes and metabolites in various diseases (such as diabetes, depression, and multiple sclerosis). The number of studies investigating the effectiveness of exercise as a mediator of the kynurenine pathway in the field of cancer is very limited. In this traditional review, current knowledge of exercise-induced modulations of the kynurenine pathway, the underlying mechanisms, as well as the relationship between exercise-induced kynurenine pathway and exercise/ cancer will be examined.

Anahtar Kelimeler

• Kynurenine
• tryptophan
• cancer
• exercise

Kanserde Kinürenin Yolağı Modülatörü Olarak Egzersiz: Geleneksel Derleme

Öz

Kanserde kinürenin yolağının ilgili enzimlerinin aşırı aktivasyonu ve kimyasal dönüşüm metabolitlerinin kan serum seviyelerindeki artışı, mutant hücrelerin hayatta kalması ve çevre dokuları istila etmesi için immünolojik olarak duyarlı bir mikro ortam sağlar. Özellikle indoleamin 2,3-dioksijenaz 1 aşırı aktivasyonunun gastrointestinal kanserler, jinekolojik kanserler, hematolojik maligniteler, meme kanseri, akciğer kanseri, glioma, melanom, prostat ve pankreas kanseri gibi çeşitli kanserlerde hastalığın patogenezinin ve kötü prognozunun bir belirleyicisi olarak rol oynadığı düşünülmektedir. Ek olarak, kinürenik asitin, beyin omurilik sıvısındaki kinolinik asit konsantrasyonlarını artırarak inflamasyona yol açtığı ve depresif semptomlara yol açtığı gösterilmiştir. Bu bağlamda tümör oluşumu, prognozu, kanserin kendisine veya tedavilerine bağlı oluşan yan etkilerin açıklanmasında kinürenin yolağı metabolitleri ile ilgili araştırmalar hız kazanmıştır. Önceki çalışmalarda hem akut hem de kronik egzersizin, çeşitli hastalıklarda (diyabet, depresyon, multiple skleroz gibi) kinürenin yolağı enzimleri ve metabolitleri üzerine up/down regülasyona neden olabileceği gösterilmiştir. Kinürenin yolağının mediatörü olarak egzersizin etkinliğini kanser alanında araştıran çalışma sayısı oldukça kısıtlıdır. Bu geleneksel derlemede, kinürenin yolağının egzersize bağlı modülasyonları ile ilgili mevcut bilgiler, altta yatan mekanizmalar ayrıca egzersizle indüklenen kinürenin yolağı ve egzersiz/kanser ilişkisi incelenecektir.

Anahtar Kelimeler

• Kinürenin triptofan
• kanser
• egzersiz

Kaynakça

1. Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health. Science (New York, NY). 2017 Jul 28;357(6349).
2. Hargreaves K, Pardridge W. Neutral amino acid transport at the human blood-brain barrier. J Biol Chem. 1988 Dec;263(36):19392-7.
3. Davis I, Liu A. What is the tryptophan kynurenine pathway and why is it important to neurotherapeutics? Expert Rev Neurother. 2015 May;15(7):719-21.
4. Badawy AA. Tryptophan availability for kynurenine pathway metabolism across the life span: Control mechanisms and focus on aging, exercise, diet and nutritional supplements. Neuropharmacology. 2017 Jan;112(Pt B):248-63.
5. Schwarcz R, Stone TW. The kynurenine pathway and the brain: Challenges, controversies and promises. Neuropharmacology. 2017 Jan;112(Pt B):237-47.
6. Hayaishi O. My life with tryptophan—never a dull moment. Protein Sci. 1993 Mar;2(3):472-5.
7. Vécsei L, Szalárdy L, Fülöp F, Toldi J. Kynurenines in the CNS: recent advances and new questions. Nat Rev Drug Discov. 2013 Jan;12(1):64-82.
8. Campbell BM, Charych E, Lee AW, Moller T. Kynurenines in CNS disease: regulation by inflammatory cytokines. Front Neurosci. 2014 Feb;8:12.

9. Platten M, Nollen EA, Röhrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov. 2019 May;18(5):379-401.
10. Zimmer P, Joisten N, Schenk A, Bloch W. Impact of physical exercise on the kynurenine pathway in patients with cancer: current limitations and future perspectives. Acta Oncol. 2019 Aug;58(8):1116-7.
11. Agudelo LZ, Femenía T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, et al. Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. J Cell. 2014 Sep;159(1):33-45.
12. Serafini G, Adavastro G, Canepa G, Capobianco L, Conigliaro C, Pittaluga F, et al. Abnormalities in Kynurenine Pathway Metabolism in Treatment-Resistant Depression and Suicidality: A Systematic Review. CNS Neurol Disord Drug Targets. 2017;16(4):440-53.
13. Ebede CC, Jang Y, Escalante CP. Cancer-Related Fatigue in Cancer Survivorship. Med Clin North Am. 2017 Nov;101(6):1085-97.
14. Chung DJ, Rossi M, Romano E, Ghith J, Yuan J, Munn DH, et al. Indoleamine 2, 3-dioxygenase–expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. J Blood. 2009 Jul;114(3):555-63.
15. Wirthgen E, Hoeflich A, Rebl A, Gunther J. Kynurenic Acid: The Janus- Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions. Front Immunol. 2017 Jan;8:1957.
16. Hornyak L, Dobos N, Koncz G, Karanyi Z, Pall D, Szabo Z, et al. The Role of Indoleamine-2,3-Dioxygenase in Cancer Development, Diagnostics, and Therapy. Front Immunol. 2018 Jan;9:151.
17. Hascitha J, Priya R, Jayavelu S, Dhandapani H, Selvaluxmy G, Sunder Singh S, et al. Analysis of Kynurenine/Tryptophan ratio and expression of IDO1 and 2 mRNA in tumour tissue of cervical cancer patients. Clin Biochem. 2016 Aug;49(12):919-24.
18. Dantzer R. Role of the Kynurenine Metabolism Pathway in Inflammation-Induced Depression: Preclinical Approaches. Curr Top Behav Neurosci. 2017 Oct;31:117-38.
19. Wefel JS, Kesler SR, Noll KR, Schagen SB. Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults. CA Cancer J Clin. 2015 Mar;65(2):123-38.
20. Ebede CC, Jang Y, Escalante CP. Cancer-Related Fatigue in Cancer Survivorship. Med Clin North Am. 2017 Nov;101(6):1085-97.
21. Wefel JS, Kesler SR, Noll KR, Schagen SB. Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults. CA Cancer J Clin. 2015 Mar;65(2):123-38.
22. Cormie P, Zopf EM, Zhang X, Schmitz KH. The Impact of Exercise on Cancer Mortality, Recurrence, and Treatment-Related Adverse Effects. Epidemiol Rev. 2017 Jan 1;39(1):71-92.
23. Eschke R-CK-R, Lampit A, Schenk A, Javelle F, Steindorf K, Diel P, et al. Impact of physical exercise on growth and progression of cancer in rodents—a systematic review and meta-analysis. J Front Oncol. 2019 Feb;9:35.
24. Devin JL, Hill MM, Mourtzakis M, Quadrilatero J, Jenkins DG, Skinner TL. Acute high intensity interval exercise reduces colon cancer cell growth. T J Physiol. 2019 Apr;597(8):2177-84.
25. Li Y, Xiao X, Zhang Y, Tang W, Zhong D, Liu T, et al. Effect of Exercise on Breast Cancer: A Systematic Review and Meta-analysis of Animal Experiments. F Front Mol Biosci. 2022 Jun;9:843810.
26. Tilz GP, Domej W, Diez-Ruiz A, Weiss G, Brezinschek R, Brezinschek HP, et al. Increased immune activation during and after physical exercise. Immunobiology. 1993 Jun;188(1-2):194-202.
27. Fischer CP. Interleukin-6 in acute exercise and training: what is the biological relevance? Exerc Immunol Rev. 2006 Sept;12:6-33.
28. Hojman P, Gehl J, Christensen JF, Pedersen BK. Molecular Mechanisms Linking Exercise to Cancer Prevention and Treatment. Cell Metab. 2018 Jan 9;27(1):10-21.
29. Kasapis C, Thompson PD. The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review. J Am Coll Cardiol. 2005 May 17;45(10):1563-9.
30. Ziegler AK, Damgaard A, Mackey AL, Schjerling P, Magnusson P, Olesen AT, et al. An anti-inflammatory phenotype in visceral adipose tissue of old lean mice, augmented by exercise. Sci Rep. 2019 Aug 19;9(1):12069.
31. Clemente-Suárez VJ, Martín-Rodríguez A, Redondo-Flórez L, Ruisoto P, Navarro-Jiménez E, Ramos-Campo DJ, et al. Metabolic Health, Mitochondrial Fitness, Physical Activity, and Cancer. Cancers. 2023 Jan 28;15(3).
32. Guo C, Sun L, Chen X, Zhang D. Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural regeneration research. 2013 Jul 25;8(21):2003-14.
33. Locasale JW, Cantley LC. Altered metabolism in cancer. BMC biology. 2010 Jun 25;8:88.
34. Kim YM, Ji ES, Kim SH, Kim TW, Ko IG, Jin JJ, et al. Treadmill exercise improves short-term memory by enhancing hippocampal cell proliferation in quinolinic acid-induced Huntington's disease rats. Journal of exercise rehabilitation. 2015 Feb;11(1):5-11.
35. Joisten N, Kummerhoff F, Koliamitra C, Schenk A, Walzik D, Hardt L, et al. Exercise and the Kynurenine pathway: Current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training. Exercise immunology review. 2020;26:24-42.
36. Bansi J, Koliamitra C, Bloch W, Joisten N, Schenk A, Watson M, et al. Persons with secondary progressive and relapsing remitting multiple sclerosis reveal different responses of tryptophan metabolism to acute endurance exercise and training. Journal of neuroimmunology. 2018 Jan 15;314:101-5.
37. Millischer V, Erhardt S, Ekblom O, Forsell Y, Lavebratt C. Twelve-week physical exercise does not have a long-lasting effect on kynurenines in plasma of depressed patients. Neuropsychiatric disease and treatment. 2017;13:967-72.
38. Hennings A, Schwarz MJ, Riemer S, Stapf TM, Selberdinger VB, Rief W. Exercise affects symptom severity but not biological measures in depression and somatization - results on IL-6, neopterin, tryptophan, kynurenine and 5-HIAA. Psychiatry research. 2013 Dec 30;210(3):925-33.
39. Suhr F, Gehlert S, Grau M, Bloch W. Skeletal muscle function during exercise—fine-tuning of diverse subsystems by nitric oxide. Int J Mol Sci. 2013 Mar;14(4):7109-39.
40. Green DJ, Maiorana A, O'Driscoll G, Taylor R. Effect of exercise training on endothelium-derived nitric oxide function in humans. J Physiol. 2004 Nov 15;561(Pt 1):1-25.
41. Baskurt OK, Ulker P, Meiselman HJ. Nitric oxide, erythrocytes and exercise. Clin Hemorheol Microcirc. 2011 June;49(1-4):175-81.
42. Wink DA, Hines HB, Cheng RY, Switzer CH, Flores-Santana W, Vitek MP, et al. Nitric oxide and redox mechanisms in the immune response. J Leukoc Biol. 2011 Jun;89(6):873-91.
43. Strasser B, Geiger D, Schauer M, Gatterer H, Burtscher M, Fuchs D. Effects of Exhaustive Aerobic Exercise on Tryptophan-Kynurenine Metabolism in Trained Athletes. PLoS One.2016 Apr;11(4):e0153617.
44. Metcalfe AJ, Koliamitra C, Javelle F, Bloch W, Zimmer P. Acute and chronic effects of exercise on the kynurenine pathway in humans - A brief review and future perspectives. Physiol Behav. 2018 Oct 1;194:583-7.
45. Joisten N, Schumann M, Schenk A, Walzik D, Freitag N, Knoop A, et al. Acute hypertrophic but not maximal strength loading transiently enhances the kynurenine pathway towards kynurenic acid. Eur J Appl Physiol. 2020 Jun;120(6):1429-36.
46. Schenk A, Esser T, Knoop A, Thevis M, Herden J, Heidenreich A, et al. Effect of a Single Bout of Aerobic Exercise on Kynurenine Pathway Metabolites and Inflammatory Markers in Prostate Cancer Patients—A Pilot Randomized Controlled Trial. Metabolites. 2020 Dec;11(1):4.
47. Walsh NP, Gleeson M, Shephard RJ, Gleeson M, Woods JA, Bishop NC, et al. Position statement. Part one: Immune function and exercise. Exerc Immunol Rev. 2011 Jun;17:6-63.
48. Hötting K, Schickert N, Kaiser J, Röder B, Schmidt-Kassow M. The effects of acute physical exercise on memory, peripheral BDNF, and cortisol in young adults. Neural Plast. 2016 Jun;686057348. Hötting K, Schickert N, Kaiser J, Röder B, Schmidt-Kassow M. The effects of acute physical exercise on memory, peripheral BDNF, and cortisol in young adults. Neural Plast. 2016;2016.
49. O'Leary CB, Hackney AC. Acute and chronic effects of resistance exercise on the testosterone and cortisol responses in obese males: a systematic review. Physiol Res. 2014 August;63(6):693-704.
50. Joisten N, Walzik D, Metcalfe AJ, Bloch W, Zimmer P. Physical Exercise as Kynurenine Pathway Modulator in Chronic Diseases: Implications for Immune and Energy Homeostasis. International journal of tryptophan research : Int J Tryptophan Res. 2020 Jul 8;13:1178646920938688
51. Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo MA. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol. 2011 Aug 5;11(9):607-15.
52. Ballor DL, Poehlman ET. Exercise-training enhances fat-free mass preservation during diet-induced weight loss: a meta-analytical finding. Int J Obes Relat Metab Disord. 1994 Jan;18(1):35-40.
53. Zimmer P, Schmidt ME, Prentzell MT, Berdel B, Wiskemann J, Kellner KH, et al. Resistance Exercise Reduces Kynurenine Pathway Metabolites in Breast Cancer Patients Undergoing Radiotherapy. Front Oncol.2019 Sep 25;9:962
54. Pal A, Zimmer P, Clauss D, Schmidt ME, Ulrich CM, Wiskemann J, et al. Resistance Exercise Modulates Kynurenine Pathway in Pancreatic Cancer Patients. I Int J Sports Med.2021 Jan;42(1):33-40.
55. Richardson RS, Noyszewski EA, Kendrick KF, Leigh JS, Wagner PD. Myoglobin O2 desaturation during exercise. Evidence of limited O2 transport. J Clin Invest. 1995 Oct;96(4):1916-26.
56. Thomas SR, Terentis AC, Cai H, Takikawa O, Levina A, Lay PA, et al. Post-translational regulation of human indoleamine 2,3-dioxygenase activity by nitric oxide. J Biol Chem. 2007 Aug 17;282(33):23778-87.
57. Hondares E, Rosell M, Díaz-Delfín J, Olmos Y, Monsalve M, Iglesias R, et al. Peroxisome proliferator-activated receptor α (PPARα) induces PPARγ coactivator 1α (PGC-1α) gene expression and contributes to thermogenic activation of brown fat: involvement of PRDM16. J Biol Chem. 2011 Dec;286(50):43112-22.
58. Agudelo LZ, Femenía T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, et al. Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. J Cell. 2014 Sep;159(1):33-45.
59. Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol. 2002 Oct;2(10):748-59.
60. Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005 Sept;1(6):361- 70.
61. Ruas JL, White JP, Rao RR, Kleiner S, Brannan KT, Harrison BC, et al. A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy. J Cell. 2012 Oct;151(6):1319-31.