Helpt u ons aan 500 donateurs?

25 november 2017: Bron: Nat Commun. 2017; 8: 922. Published online 2017 Oct 13.

Er wordt vaak gezegd dat suiker kanker veroorzaakt of erger maakt en de tumor laat groeien. Hiervoor was tot nu toe echter geen wetenschappelijk bewijs. Maar nu lijken Belgische onderzoekers ontrafelt te hebben dat suiker de groei van de tumor stimuleert en wel degelijk kanker agressiever maakt. Zelfs tijdens een chemokuur voedt suiker de tumorcellen extra waardoor de effectiviteit van chemo gedeeltelijk teniet wordt gedaan door de suiker. Of suiker ook kanker veroorzaakt zijn ze minder stellig want een gezond lichaam kan een heleboel repareren. Dit blijkt uit een 9 jaar lang onderzoek naar het Warburg effect van onderzoekers aan het Vlaams Instituut voor Biotechnologie (VIB), KULeuven en VUB. Zij legden bloot hoe kankercellen suiker versneld afbreken en hoe dat ­mechanisme er dan weer voor zorgt dat de kanker in stand wordt gehouden en er weer recidieven ontstaan en uitzaaiingen, vaak elders in het lichaam, opduiken.

“Het is een belangrijke doorbraak in het kankeronderzoek en een suikervrij of suikerarm dieet is voor een kanker­­pa­tiënt dus geen overbodige luxe”, zegt professor Johan Thevelein, mede onderderzoeker van deze studie: Fructose-1,6-bisphosphate couples glycolytic flux to activation of Ras.

In 2008 besloten prof. Thevelein en collega's om onderzoek te doen naar het zogeheten Warburg-effect. “Dr. Otto Warburg, een Duitse biochemicus, (het Houtsmullerdieet is mede gebaseerd op het Warburg effect), ontdekte al eindjaren dertig vorige eeuw dat kankercellen versneld suiker omzetten in melkzuur.

Prof. Thevelein: “Ze verkiezen eigenlijk suiker te vergisten naar melkzuur bóven te verademen naar koolstofdioxide.” Compleet het tegenovergestelde van gezonde cellen. “Hoe agressiever de kanker, hoe sneller die cellen dat doen. Maar waarom ze dat deden en of dat Warburg-effect louter een symptoom is van de kanker of er ook een invloed op uitoefent, dat wisten we niet. Wij wilden dat achterhalen.”

In het onderzoek werd eerst gekeken naar gistcellen. Een eenvoudige celvorm, die ook het Warburg-effect vertoont zegt prof. Thevelein, maar dan zonder de invloed van hormonen en andere regulatiesystemen die in kankercellen bij mensen de resultaten zouden kunnen vertroebelen.

"Nu wordt het even heel technisch", aldus prof. Thevelein: “In de gistcellen ontdekten we hoe bij die omzetting van suiker de molecule fructose 1,6-biofosfaat sterker in de cellen aangemaakt wordt. Die activeert dan weer een proteïne (eiweit) dat de cellen op hun beurt doet vermenigvuldigen. Dat mechanisme is daarna op de faculteit geneeskunde in menselijke kankercellen bevestigd”, zegt professor Thevelein.

"Ook voor kankercellen betekent het dus dat suiker kankercellen nog sneller doet vermenigvuldigen. De tumor groeit; de kanker wordt agressiever en deelt sneller. Met als effect dat er nog meer kankercellen suiker gaan omzetten. “Het is dus een vicieuze cirkel, die maakt dat de kanker moeilijker met geneesmiddelen te bestrijden is.”

Prof. Johan Thevelein is heel stellig over een suikerarm dieet voor kankerpatiënten: “Een suikervrij of suikerarm dieet blijkt niet zomaar een hype maar écht iets om op in te zetten bij kankerpatiënten. Het kan helpen de kanker te overwinnen en chemotherapie veel effectiever maken. Vooral ook omdat patiënten naast chemokuren soms extra voeding krijgen toegediend om aan te sterken. En die bevatten meestal veel glucosesuiker.”

Of suiker ook kanker kan veroorzaken en preventief kanker kan voorkomen is hij minder stellig: “Daarvoor is nog meer onderzoek nodig. Normale cellen hebben goede controlesystemen die ervoor zorgen dat de suikerafbraak in de cel binnen de perken blijft. Ze kunnen er doorgaans mee overweg. Of dat ook bij langdurige excessieve suikerinname zo is, blijft onduidelijk.”

Het studierapport is gepublicered in Nature: Fructose-1,6-bisphosphate couples glycolytic flux to activation of Ras.  en gratis in te zien.

CNN had een mooie reportage over de studie van prof Thevelein en collega's: Does sugar, which makes all things delicious, lead to cancer?

Hier het abstract van de studie met referentieliijst:

Sugar stimulates the aggressiveness of cancer

Nat Commun. 2017; 8: 922.
Published online 2017 Oct 13. doi:  10.1038/s41467-017-01019-z
PMCID: PMC5640605

Fructose-1,6-bisphosphate couples glycolytic flux to activation of Ras

Abstract

Yeast and cancer cells share the unusual characteristic of favoring fermentation of sugar over respiration. We now reveal an evolutionary conserved mechanism linking fermentation to activation of Ras, a major regulator of cell proliferation in yeast and mammalian cells, and prime proto-oncogene product. A yeast mutant (tps1∆) with overactive influx of glucose into glycolysis and hyperaccumulation of Fru1,6bisP, shows hyperactivation of Ras, which causes its glucose growth defect by triggering apoptosis. Fru1,6bisP is a potent activator of Ras in permeabilized yeast cells, likely acting through Cdc25. As in yeast, glucose triggers activation of Ras and its downstream targets MEK and ERK in mammalian cells. Biolayer interferometry measurements show that physiological concentrations of Fru1,6bisP stimulate dissociation of the pure Sos1/H-Ras complex. Thermal shift assay confirms direct binding to Sos1, the mammalian ortholog of Cdc25. Our results suggest that the Warburg effect creates a vicious cycle through Fru1,6bisP activation of Ras, by which enhanced fermentation stimulates oncogenic potency.

References

1. Diaz-Ruiz R, Uribe-Carvajal S, Devin A, Rigoulet M. Tumor cell energy metabolism and its common features with yeast metabolism. Biochim. Biophys. Acta. 2009;1796:252–265. [PubMed]
2. Warburg O. On the origin of cancer cells. Science. 1956;123:309–314. doi: 10.1126/science.123.3191.309. [PubMed] [Cross Ref]
3. Mathupala SP, Rempel A, Pedersen PL. Aberrant glycolytic metabolism of cancer cells: a remarkable coordination of genetic, transcriptional, post-translational, and mutational events that lead to a critical role for type II hexokinase. J. Bioenerg. Biomembr. 1997;29:339–343. doi: 10.1023/A:1022494613613. [PubMed] [Cross Ref]
4. Weber G, Lea MA. The molecular correlation concept of neoplasia. Adv. Enzyme Regul. 1966;4:115–145. doi: 10.1016/0065-2571(66)90011-2. [PubMed] [Cross Ref]
5. Upadhyay M, Samal J, Kandpal M, Singh OV, Vivekanandan P. The Warburg effect: insights from the past decade. Pharmacol. Ther. 2013;137:318–330. doi: 10.1016/j.pharmthera.2012.11.003. [PubMed] [Cross Ref]
6. Thevelein JM, de Winde JH. Novel sensing mechanisms and targets for the cAMP-protein kinase A pathway in the yeast Saccharomyces cerevisiae. Mol. Microbiol. 1999;33:904–918. doi: 10.1046/j.1365-2958.1999.01538.x. [PubMed] [Cross Ref]
7. van Dam TJ, Bos JL, Snel B. Evolution of the Ras-like small GTPases and their regulators. Small GTPases. 2011;2:4–16. doi: 10.4161/sgtp.2.1.15113. [PMC free article] [PubMed] [Cross Ref]
8. van Dam TJ, Rehmann H, Bos JL, Snel B. Phylogeny of the CDC25 homology domain reveals rapid differentiation of Ras pathways between early animals and fungi. Cell Signal. 2009;21:1579–1585. doi: 10.1016/j.cellsig.2009.06.004. [PubMed] [Cross Ref]
9. Kataoka T, et al. Functional homology of mammalian and yeast RAS genes. Cell. 1985;40:19–26. doi: 10.1016/0092-8674(85)90304-6. [PubMed] [Cross Ref]
10. Broek D, et al. Differential activation of yeast adenylate cyclase by wild-type and mutant RAS proteins. Cell. 1985;41:763–769. doi: 10.1016/S0092-8674(85)80057-X. [PubMed] [Cross Ref]
11. Gourlay CW, Ayscough KR. Actin-induced hyperactivation of the Ras signaling pathway leads to apoptosis in Saccharomyces cerevisiae. Mol. Cell. Biol. 2006;26:6487–6501. doi: 10.1128/MCB.00117-06. [PMC free article] [PubMed] [Cross Ref]
12. Barbacid M. ras genes. Annu. Rev. Biochem. 1987;56:779–827. doi: 10.1146/annurev.bi.56.070187.004023. [PubMed] [Cross Ref]
13. Mbonyi K, Beullens M, Detremerie K, Geerts L, Thevelein JM. Requirement of one functional RAS gene and inability of an oncogenic ras variant to mediate the glucose-induced cyclic AMP signal in the yeast Saccharomyces cerevisiae. Mol. Cell. Biol. 1988;8:3051–3057. doi: 10.1128/MCB.8.8.3051. [PMC free article] [PubMed] [Cross Ref]
14. Colombo S, et al. Involvement of distinct G-proteins, Gpa2 and Ras, in glucose- and intracellular acidification-induced cAMP signalling in the yeast Saccharomyces cerevisiae. EMBO J. 1998;17:3326–3341. doi: 10.1093/emboj/17.12.3326. [PMC free article] [PubMed] [Cross Ref]
15. Colombo S, Ronchetti D, Thevelein JM, Winderickx J, Martegani E. Activation state of the Ras2 protein and glucose-induced signaling in Saccharomyces cerevisiae. J. Biol. Chem. 2004;279:46715–46722. doi: 10.1074/jbc.M405136200. [PubMed] [Cross Ref]
16. Rolland F, et al. Glucose-induced cAMP signalling in yeast requires both a G-protein coupled receptor system for extracellular glucose detection and a separable hexose kinase-dependent sensing process. Mol. Microbiol. 2000;38:348–358. doi: 10.1046/j.1365-2958.2000.02125.x. [PubMed] [Cross Ref]
17. van Aelst L, Jans AW, Thevelein JM. Involvement of the CDC25 gene product in the signal transmission pathway of the glucose-induced RAS-mediated cAMP signal in the yeast Saccharomyces cerevisiae. J. Gen. Microbiol. 1991;137:341–349. doi: 10.1099/00221287-137-2-341. [PubMed] [Cross Ref]
18. Paiardi C, Belotti F, Colombo S, Tisi R, Martegani E. The large N-terminal domain of Cdc25 protein of the yeast Saccharomyces cerevisiae is required for glucose-induced Ras2 activation. FEMS Yeast Res. 2007;7:1270–1275. doi: 10.1111/j.1567-1364.2007.00300.x. [PubMed] [Cross Ref]
19. Beullens M, et al. Studies on the mechanism of the glucose-induced cAMP signal in glycolysis and glucose repression mutants of the yeast Saccharomyces cerevisiae. Eur. J. Biochem. 1988;172:227–231. doi: 10.1111/j.1432-1033.1988.tb13877.x. [PubMed] [Cross Ref]
20. Hers HG. The discovery and the biological role of fructose 2,6-bisphosphate. Biochem. Soc. Trans. 1984;12:729–735. doi: 10.1042/bst0120729. [PubMed] [Cross Ref]
21. Herling A, Konig M, Bulik S, Holzhutter HG. Enzymatic features of the glucose metabolism in tumor cells. FEBS J. 2011;278:2436–2459. doi: 10.1111/j.1742-4658.2011.08174.x. [PubMed] [Cross Ref]
22. Yalcin A, Telang S, Clem B, Chesney J. Regulation of glucose metabolism by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases in cancer. Exp. Mol. Pathol. 2009;86:174–179. doi: 10.1016/j.yexmp.2009.01.003. [PubMed] [Cross Ref]
23. Bustamante E, Pedersen PL. High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc. Natl Acad. Sci. USA. 1977;74:3735–3739. doi: 10.1073/pnas.74.9.3735. [PMC free article] [PubMed] [Cross Ref]
24. Bustamante E, Morris HP, Pedersen PL. Energy metabolism of tumor cells. Requirement for a form of hexokinase with a propensity for mitochondrial binding. J. Biol. Chem. 1981;256:8699–8704. [PubMed]
25. Wilson JE. Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J. Exp. Biol. 2003;206:2049–2057. doi: 10.1242/jeb.00241. [PubMed] [Cross Ref]
26. Blazquez MA, Lagunas R, Gancedo C, Gancedo JM. Trehalose-6-phosphate, a new regulator of yeast glycolysis that inhibits hexokinases. FEBS Lett. 1993;329:51–54. doi: 10.1016/0014-5793(93)80191-V. [PubMed] [Cross Ref]
27. Thevelein JM, Hohmann S. Trehalose synthase: guard to the gate of glycolysis in yeast? Trends Biochem. Sci. 1995;20:3–10. doi: 10.1016/S0968-0004(00)88938-0. [PubMed] [Cross Ref]
28. Van Aelst L, et al. Molecular cloning of a gene involved in glucose sensing in the yeast Saccharomyces cerevisiae. Mol. Microbiol. 1993;8:927–943. doi: 10.1111/j.1365-2958.1993.tb01638.x. [PubMed] [Cross Ref]
29. Neves MJ, et al. Control of glucose influx into glycolysis and pleiotropic effects studied in different isogenic sets of Saccharomyces cerevisiae mutants in trehalose biosynthesis. Curr. Genet. 1995;27:110–122. doi: 10.1007/BF00313424. [PubMed] [Cross Ref]
30. Hohmann S, et al. The growth and signalling defects of the ggs1 (fdp1/byp1) deletion mutant on glucose are suppressed by a deletion of the gene encoding hexokinase PII. Curr. Genet. 1993;23:281–289. doi: 10.1007/BF00310888. [PubMed] [Cross Ref]
31. Petitjean M, Teste MA, Leger-Silvestre I, Francois JM, Parrou JL. A new function for the yeast trehalose-6P synthase (Tps1) protein, as key pro-survival factor during growth, chronological ageing, and apoptotic stress. Mech. Ageing Dev. 2017;161:234–246. doi: 10.1016/j.mad.2016.07.011. [PubMed] [Cross Ref]
32. Hortner H, et al. Regulation of synthesis of catalases and iso-1-cytochrome c in Saccharomyces cerevisiae by glucose, oxygen and heme. Eur. J. Biochem. 1982;128:179–184. doi: 10.1111/j.1432-1033.1982.tb06949.x. [PubMed] [Cross Ref]
33. Sass P, Field J, Nikawa J, Toda T, Wigler M. Cloning and characterization of the high-affinity cAMP phosphodiesterase of Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA. 1986;83:9303–9307. doi: 10.1073/pnas.83.24.9303. [PMC free article] [PubMed] [Cross Ref]
34. van Heerden JH, et al. Lost in transition: start-up of glycolysis yields subpopulations of nongrowing cells. Science. 2014;343:1245114. doi: 10.1126/science.1245114. [PubMed] [Cross Ref]
35. Noubhani A, Bunoust O, Rigoulet M, Thevelein JM. Reconstitution of ethanolic fermentation in permeabilized spheroplasts of wild-type and trehalose-6-phosphate synthase mutants of the yeast Saccharomyces cerevisiae. Eur. J. Biochem. 2000;267:4566–4576. doi: 10.1046/j.1432-1327.2000.01511.x. [PubMed] [Cross Ref]
36. Boy-Marcotte E, Ikonomi P, Jacquet M. SDC25, a dispensable Ras guanine nucleotide exchange factor of Saccharomyces cerevisiae differs from CDC25 by its regulation. Mol. Biol. Cell. 1996;7:529–539. doi: 10.1091/mbc.7.4.529. [PMC free article] [PubMed] [Cross Ref]
37. Tanaka K, et al. S. cerevisiae genes IRA1 and IRA2 encode proteins that may be functionally equivalent to mammalian ras GTPase activating protein. Cell. 1990;60:803–807. doi: 10.1016/0092-8674(90)90094-U. [PubMed] [Cross Ref]
38. Van Aelst L, Boy-Marcotte E, Camonis JH, Thevelein JM, Jacquet M. The C-terminal part of the CDC25 gene product plays a key role in signal transduction in the glucose-induced modulation of cAMP level in Saccharomyces cerevisiae. Eur. J. Biochem. 1990;193:675–680. doi: 10.1111/j.1432-1033.1990.tb19386.x. [PubMed] [Cross Ref]
39. Schomerus C, Munder T, Kuntzel H. Site-directed mutagenesis of the Saccharomyces cerevisiae CDC25 gene: effects on mitotic growth and cAMP signalling. Mol. Gen. Genet. 1990;223:426–432. doi: 10.1007/BF00264449. [PubMed] [Cross Ref]
40. Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, Kuriyan J. The structural basis of the activation of Ras by Sos. Nature. 1998;394:337–343. doi: 10.1038/28548. [PubMed] [Cross Ref]
41. Huberts DH, Niebel B, Heinemann M. A flux-sensing mechanism could regulate the switch between respiration and fermentation. FEMS Yeast Res. 2012;12:118–128. doi: 10.1111/j.1567-1364.2011.00767.x. [PubMed] [Cross Ref]
42. Marin-Hernandez A, et al. Modeling cancer glycolysis. Biochim. Biophys. Acta. 2011;1807:755–767. doi: 10.1016/j.bbabio.2010.11.006. [PubMed] [Cross Ref]
43. Mazurek S, Zwerschke W, Jansen-Durr P, Eigenbrodt E. Metabolic cooperation between different oncogenes during cell transformation: interaction between activated ras and HPV-16 E7. Oncogene. 2001;20:6891–6898. doi: 10.1038/sj.onc.1204792. [PubMed] [Cross Ref]
44. Niesen FH, Berglund H, Vedadi M. The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability. Nat. Protoc. 2007;2:2212–2221. doi: 10.1038/nprot.2007.321. [PubMed] [Cross Ref]
45. Boles E, Gohlmann HW, Zimmermann FK. Cloning of a second gene encoding 5-phosphofructo-2-kinase in yeast, and characterization of mutant strains without fructose-2,6-bisphosphate. Mol. Microbiol. 1996;20:65–76. doi: 10.1111/j.1365-2958.1996.tb02489.x. [PubMed] [Cross Ref]
46. Kole HK, Resnick RJ, Van Doren M, Racker E. Regulation of 6-phosphofructo-1-kinase activity in ras-transformed rat-1 fibroblasts. Arch. Biochem. Biophys. 1991;286:586–590. doi: 10.1016/0003-9861(91)90084-V. [PubMed] [Cross Ref]
47. Telang S, et al. Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene. 2006;25:7225–7234. doi: 10.1038/sj.onc.1209709. [PubMed] [Cross Ref]
48. Hu Y, et al. K-ras(G12V) transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. Cell Res. 2012;22:399–412. doi: 10.1038/cr.2011.145. [PMC free article] [PubMed] [Cross Ref]
49. Lo CH, Farina F, Morris HP, Weinhouse S. Glycolytic regulation in rat liver and hepatomas. Adv. Enzyme Regul. 1968;6:453–464. doi: 10.1016/0065-2571(68)90028-9. [PubMed] [Cross Ref]
50. Li B, et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature. 2014;513:251–255. doi: 10.1038/nature13557. [PMC free article] [PubMed] [Cross Ref]
51. Zhu Y, et al. NPM1 activates metabolic changes by inhibiting FBP1 while promoting the tumorigenicity of pancreatic cancer cells. Oncotarget. 2015;6:21443–21451. doi: 10.18632/oncotarget.4167. [PMC free article] [PubMed] [Cross Ref]
52. Leadsham JE, et al. Whi2p links nutritional sensing to actin-dependent Ras-cAMP-PKA regulation and apoptosis in yeast. J. Cell Sci. 2009;122:706–715. doi: 10.1242/jcs.042424. [PMC free article] [PubMed] [Cross Ref]
53. Yun J, et al. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. 2015;350:1391–1396. doi: 10.1126/science.aaa5004. [PMC free article] [PubMed] [Cross Ref]
54. Lim SO, et al. EGFR signaling enhances aerobic glycolysis in triple-negative breast cancer cells to promote tumor growth and immune escape. Cancer Res. 2016;76:1284–1296. doi: 10.1158/0008-5472.CAN-15-2478. [PMC free article] [PubMed] [Cross Ref]
55. Wang M, Herrmann CJ, Simonovic M, Szklarczyk D, von Mering C. Version 4.0 of PaxDb: Protein abundance data, integrated across model organisms, tissues, and cell-lines. Proteomics. 2015;15:3163–3168. doi: 10.1002/pmic.201400441. [PubMed] [Cross Ref]
56. Nowak T, Lee MJ. Reciprocal cooperative effects of multiple ligand binding to pyruvate kinase. Biochemistry. 1977;16:1343–1350. doi: 10.1021/bi00626a016. [PubMed] [Cross Ref]
57. Averet N, Fitton V, Bunoust O, Rigoulet M, Guerin B. Yeast mitochondrial metabolism: from in vitro to in situ quantitative study. Mol. Cell. Biochem. 1998;184:67–79. doi: 10.1023/A:1006830810440. [PubMed] [Cross Ref]
58. Schmitz MH, et al. Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cells. Nat. Cell Biol. 2010;12:886–893. doi: 10.1038/ncb2092. [PMC free article] [PubMed] [Cross Ref]
59. de Koning W, van Dam K. A method for the determination of changes of glycolytic metabolites in yeast on a subsecond time scale using extraction at neutral pH. Anal. Biochem. 1992;204:118–123. doi: 10.1016/0003-2697(92)90149-2. [PubMed] [Cross Ref]
60. Madeo F, Frohlich E, Frohlich KU. A yeast mutant showing diagnostic markers of early and late apoptosis. J. Cell Biol. 1997;139:729–734. doi: 10.1083/jcb.139.3.729. [PMC free article] [PubMed] [Cross Ref]
61. Herrmann JM, Stuart RA, Craig EA, Neupert W. Mitochondrial heat shock protein 70, a molecular chaperone for proteins encoded by mitochondrial DNA. J. Cell Biol. 1994;127:893–902. doi: 10.1083/jcb.127.4.893. [PMC free article] [PubMed] [Cross Ref]
62. Ludovico P, et al. Cytochrome c release and mitochondria involvement in programmed cell death induced by acetic acid in Saccharomyces cerevisiae. Mol. Biol. Cell. 2002;13:2598–2606. doi: 10.1091/mbc.E01-12-0161. [PMC free article] [PubMed] [Cross Ref]

Articles from Nature Communications are provided here courtesy of Nature Publishing Group

Plaats een reactie ...

Reageer op "Suiker doet tumoren groeien en maakt kanker agressiever en bewijst Warburg effect. Een suikerarm dieet voor kankerpatienten is aan te bevelen aldus prof. dr. Johan M. Thevelein na zijn baanbrekende onderzoek"


Gerelateerde artikelen
 

Gerelateerde artikelen

Archief nieuwsberichten over >> Kankerpatiënten met een laag >> Nederlandse filmpremière >> Wim Hof die wereldberoemd >> Retour Hemel: documentaire >> Kankerpil - AOH1996, van professor >> Patienten met zeldzame vormen >> Sterkere MRI-scanner met nieuw >> Er dreigt een wereldwijde >> 34 procent van alle kankerpatienten >>