Mehmet Ali KISAÇAM, Penbe Sema TEMİZER OZAN

Kanser Hücrelerinin Metabolik İhtiyaçları ve Bağımlılıkları

Kanser, hücrelerin aşırı ve zamansız çoğalmalarına yol açan metabolik ve davranışsal değişiklikler geçirdikleri, çok basamaklı bir süreçtir. Kanserli hücrelerin gelişmesi için hücrelerde sinyalizasyon, apoptozis ve sınırlı bölünme mekanizmalarının bozulması gerekmektedir. Normal hücreler dinlenme safhasında sadece enerji üretirken prolifere olan hücreler enerji üretiminin yanında makro molekülleri sentezlemeli ve hücresel redoks dengesini korumalıdırlar. Kanser hücreleri, atipik metabolik özellik gösterir. Hızlı prolifere olan tümörler, bir molekül glikozdan elde edilecek ATP miktarının çok az olmasına rağmen glikozu aerobik ortamda laktata dönüştürmektedir. Kanser hücrelerinin bu özelliği "Warburg Etkisi" olarak adlandırılmaktadır. Bu etki artmış glikoz alımı sayesinde nükleozitlerin ve aminoasitlerin üretimine katkıda bulunmakta ve enerji üretimi için hızlı bir yol oluşturmaktadır. Glikozun artan alımı ve tercihi katabolizmasının laktat yönünde olmasının biyokütle birikimini desteklemeye ve prolifere olan hücrelerde redoks dengenin korunmasına yönelik olduğu ileri sürülmektedir. Glikoz metabolizmasının bu şekilde yönlendirilmesi, glikozun spesifik membran ve laktat taşıyıcıları ile glikolitik yolağın çoğu ara ürününün aşırı ekspresyonuyla, aynı zamanda glikozun laktata dönüşmesinde görev alan sorumlu enzimlerin de artışı ile sağlanmaktadır. Glikolizis çeşitli glikolitik ara ürünlerinin substrat olarak görev yaptığı diğer birçok metabolik yolakla bağlantılıdır. Yüksek glikoz alımında glikolitik yolaktan dallanmış biyosentetik ara yollara glikolitik metabolitlerin akışı önemli ölçüde artmaktadır. Bu derlemenin amacını kanser hücrelerinin sahip olduğu metabolik özelliklerin ortaya konarak tedavide hedef alınabilecek ara ürünlerin ve metabolitlerin açıklanması oluşturmaktadır.

Metabolic Requirements and Dependence of Cancer Cells

Cancer is a multistep disease leading normal cells to proliferate excessively in a timeless manner and to switch their metabolic activity. Corrupted signalling, apoptosis, and limited cell division is required for cancer cell growth. Normal resting cells should produce only ATP whereas proliferating cells should synthesize not only ATP but also macromolecules and protect cellular redox balance. It has been reported that cancer cells indicate atypical metabolic properties. Altough only a little ATP is obtained from the conversion of glucose to lactate, rapidly proliferating tumors convert glucose to lactate even in aerobic conditions. This feature of cancer cells are named as "Warburg effect". Enhanced glucose intake due to these effects contribute to the production of amino acids and nucleosides and quickly create a path for energy production. Increased intake of glucose and its preferred catabolism to lactate have been suggested to support biomass generation and to protect redox balance in proliferating cells. Branched glucose metabolism is provided with overexpression of glucose spesific membrane and lactate transporters moreover it is provided with expression of the enzymes which responsible for the conversion of glucose to lactate. Glycolysis is related to many pathways in which it serves as a substrate of various glycolytic intermediates. The flow of glycolytic metabolites to glycolysis diverted pathways increase significantly in high glucose intake. The aim of this review is to determine potential target for cancer treatment by assessing metabolic feature of cancer cells.

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1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70.
2. Hanahan D, Weinberg RA. The hallmarks of cancer: The next Generation. Cell 2011; 145: 646-674.
3. Cantor JR, Sabatini DM. Cancer cell metabolism: One hallmark, many faces. Cancer Discov 2012; 2: 881-898.
4. Vander Heiden MG, Lunt SY, Dayton TL, et al. Metabolic pathway alterations that support cell proliferation. Cold Spring Harb Symp Quant Biol 2011; 76: 325-334.
5. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer 2011; 11: 85-95.
6. Lunt SY, Vander Heiden MG, Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 2011; 27: 441-464.
7. Willem HK, Patricia LB, Chi VD. Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 2011; 11: 325-337.
8. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029- 1033.
9. Granchi C, Fancelli D, Minutolo F. An update on therapeutic opportunities offered by cancer glycolytic metabolism. Bioorg Med Chem Lett 2014; 24: 4915-4925.
10. Salamon S, Podbregar E, Kubatkac P, et al. Glucose metabolism in cancer and ischemia: Possible therapeutic consequences of the warburg effect. Nutr Cancer 2017; 69: 177-183.
11. Draoui N, Schicke O, Fernandes A, et al. Synthesis and pharmacological evaluation of carboxycoumarins as a new antitumor treatment targeting lactate transport in cancer cells. Bioorg Med Chem 2013; 21: 7107-7117.
12. Vander Heiden MG. Targeting cancer metabolism: A therapeutic window opens. Nat Rev Drug Discov 2011; 10: 671-684.
13. Adekola K, Rosen ST, Shanmugam M. Glucose transporters in cancer metabolism. Curr Opin Oncol 2012; 24: 650-654.
14. Mathupala SP, Ko YH, Pedersen PL. Hexokinase-2 bound to mitochondria: Cancer's stygian link to the "Warburg Effect" and a pivotal target for effective therapy. Semin Cancer Biol 2009; 19: 17-24.
15. Ros S, Schulze A. Balancing glycolytic flux: The role of 6- phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism. Cancer Metab 2013; 1: 8.
16. Erdamar H, Kazancı FH, Gök S. Kanserde biyokimyasal değişiklikler / biochemical changes in cancer. JCAM 2014; 430-438.
17. Patra KC, Hay N. The pentose phosphate pathway and cancer. Trends Biochem Sci 2014; 39: 347-354.
18. Alving AS, Carson PE, Flanagan CL, Ickes CE. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science 1956; 124: 484-485.
19. Kalhan SC, Hanson RW. Resurgence of serine: An often neglected but indispensable amino Acid. J Biol Chem 2012; 287: 19786-19791.
20. Amelio I, Cutruzzolá F, Antonov A, Agostini M, Melino G. Serine and glycine metabolism in cancer. Trends Biochem Sci 2014; 39: 191-198.
21. Eggleston LV, Krebs HA. Regulation of the pentose phosphate cycle. Biochem J 1974; 138: 425-435.
22. Raïs B, Comin B, Puigjaner J, et al. Oxythiamine and dehydroepiandrosterone induce a G1 phase cycle arrest in Ehrlich's tumor cells through inhibition of the pentose cycle. FEBS Lett 1999; 456: 113-118.
23. Eagle H. The specific amino acid requirements of a human carcinoma cell (Stain HeLa) in tissue culture. J Exp Med 1955; 102: 37-48.
24. Kvamme E, Svenneby G. Effect of anaerobiosis and addition of keto acids on glutamine utilization by Ehrlich ascites-tumor cells. Biochim Biophys Acta 1960; 42: 187- 188.
25. Fuchs BC, Bode BP. Stressing out over survival: Glutamine as an apoptotic modulator. J Surg Res 2006; 131: 26-40.
26. Daye D, Wellen KE. Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol 2012; 23: 362-369.
27. DeBerardinis RJ, Mancuso A, Daikhin E, et al. Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 2007; 104: 19345-19350.
28. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab 2008; 7: 11-20.
29. Gao P, Tchernyshyov I, Chang TC, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009; 458: 762-765.
30. Le A, Lane AN, Hamaker M, et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab 2012; 15: 110-121.
31. Obre E, Rossignol R. Emerging concepts in bioenergetics and cancer research: Metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy. Int J Biochem Cell Biol 2015; 59: 167-181