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Glyceraldehyde-3-phosphate, a glycolytic intermediate, plays a key role in controlling cell fate via inhibition of caspase activity

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Molecules and Cells

Abstract

Glyceraldehyde-3-phosphate is a key intermediate in several central metabolic pathways of all organisms. Aldolase and glyceraldehyde-3-phosphate dehydrogenase are involved in the production or elimination of glyceraldehyde-3-phosphate during glycolysis or gluconeogenesis, and are differentially expressed under various physiological conditions, including cancer, hypoxia, and apoptosis. In this study, we examine the effects of glyceraldehyde-3-phosphate on cell survival and apoptosis. Overexpression of aldolase protected cells against apoptosis, and addition of glyceraldehyde-3-phosphate to cells delayed apoptosis. Additionally, delayed apoptotic phenomena were observed when glyceraldehyde-3-phosphate was added to a cell-free system, in which artificial apoptotic process was induced by adding dATP and cytochrome c. Surprisingly, glyceraldehyde-3-phosphate directly suppressed caspase-3 activity in a reversible noncompetitive mode, preventing caspase-dependent proteolysis. Based on these results, we suggest that glyceraldehyde-3-phosphate, a key molecule in several central metabolic pathways, functions as a molecule switch between cell survival and apoptosis.

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References

  • Adrain, C., Creagh, E.M., Cullen, S.P., and Martin, S.J. (2004). Caspase-dependent inactivation of proteasome function during programmed cell death in drosophila and man. J. Biol. Chem. 27, 36923–36930.

    Article  CAS  Google Scholar 

  • Altenberg, B., and Greulich, K.O. (2004). Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics 84, 1014–1020.

    Article  CAS  PubMed  Google Scholar 

  • Bao, Q., and Shi, Y. (2007). Apoptosome: a platform for the activation of initiator caspases. Cell Death Differ. 14, 56–65.

    Article  CAS  PubMed  Google Scholar 

  • Chuang, D.-M., Hough, C., and Senatorov, V.V. (2005). Glyceraldehyde-3-phosphate dehydrogenase, apoptosis, and neurodegenerative diseases. Annu. Rev. Pharmacol. Toxicol. 45, 269–290.

    Article  CAS  PubMed  Google Scholar 

  • Fang, B., Boross, P., Tozser, J., and Weber, I.T. (2006). Structural and kinetic analysis of caspase-3 reveals role for S5 binding site in substrate recognition. J. Mol. Biol. 360, 654–666.

    Article  CAS  PubMed  Google Scholar 

  • Garland, J.M., and Halestrap, A. (1997). Energy metabolism during apoptosis. Bcl-2 promotes survival in hematopoietic cells induced to apoptose by growth factor withdrawal by stabilizing a form of metabolic arrest. J. Biol. Chem. 272, 4680–4688.

    Article  CAS  PubMed  Google Scholar 

  • Harlin, H., Reffey, S.B., Duckett, C.S., Lindsten, T., and Thompson, C.B. (2001). Characterization of XIAP-deficient mice. Mol. Cell. Biol. 21, 3604–3608.

    Article  CAS  PubMed  Google Scholar 

  • Hoque, M.A., Ushiyama, H., Tomita, M., and Shimizu, K. (2005). Dynamic responses of the intracellular metabolite concentrations of the wild type and pkyA mutant Escherichia coli against pulse addition of glucose or NH3 under those limiting continuous cultures. Biochem. Eng. 26, 38–49.

    Article  CAS  Google Scholar 

  • Ishitani, R., Sunaga, K., Hirano, A., Saunders, P., Katsube, N., Tanaka, M., and Chuang, D.M. (1996). Evidence that glyceraldehyde-3-phosphate dehydrogenase is involved in age-induced apoptosis in mature cerebellar granule neurons in culture. J. Neurochem. 66, 928–935.

    Article  CAS  PubMed  Google Scholar 

  • Jang, M., Park, B.C., Lee, A.Y., Na, K.S., Kang, S., Bae, K.-H., Myung, P.K., Chung, B.C., Cho, S., Lee, D.H., et al. (2007). Caspase-7 mediated cleavage of proteasome subunits during apoptosis. Biochem. Biophys. Res. Commun. 363, 388–394.

    Article  CAS  PubMed  Google Scholar 

  • Jang, M., Park, B.C., Kang, S., Lee, D.H., Cho, S., Lee, S.C., Bae, K.-H., and Park, S.G. (2008). Mining of caspase-7 substrates using a degradomic approach. Mol. Cells 26, 152–157.

    CAS  PubMed  Google Scholar 

  • Jang, M., Park, B.C., Kang, S., Chi, S.-W., Cho, S., Chung, S.J., Lee, S.C., Bae, K.-H., and Park, S.G. (2009). Far upstream element-binding protein-1, a novel caspase substrate, acts as a cross-talker between apoptosis and the c-myc oncogene. Oncogene 28, 1529–1536.

    Article  CAS  PubMed  Google Scholar 

  • Jiang, X., and Wang, X. (2000). Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to apaf-1. J. Biol. Chem. 275, 31199–31203.

    Article  CAS  PubMed  Google Scholar 

  • Kass, G.E., Eriksson, J.E., Weis, M., Orrenius, S., and Chow, S.C. (1996). Chromatin condensation during apoptosis requires ATP. Biochem. J. 318, 749–752.

    CAS  PubMed  Google Scholar 

  • Kilic, M., Kasperczyk, H., Fulda, S., and Debatin, K.-M. (2007). Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance. Oncogene 26, 2027–2038.

    Article  CAS  PubMed  Google Scholar 

  • Kumar, S. (2007). Caspase function in programmed cell death. Cell Death Differ. 14, 32–43.

    Article  CAS  PubMed  Google Scholar 

  • Lee, A.Y., Park, B.C., Jang, M., Cho, S., Lee, D.H., Lee, S.C., Myung, P.K., and Park, S.G. (2004). Identification of caspase-3 degradome by two-dimensional gel electrophoresis and matrixassisted laser desorption/ionization-time of flight analysis. Proteomics 4, 3429–3436.

    Article  CAS  PubMed  Google Scholar 

  • Leist, M., Single, B., Castoldi, A.F., Kuhnle, S., and Nicotera, P. (1997). Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J. Exp. Med. 185, 1481–1486.

    Article  CAS  PubMed  Google Scholar 

  • Li, C., Xiao, Z., Zhang, X., Li, J., Li, X., Yi, H., Li, M., Zhu, G., and Liang, S. (2006). Proteome analysis of human lung squamous carcinoma. Proteomics 6, 547–558.

    Article  CAS  PubMed  Google Scholar 

  • Lu, H., Forbes, R.A., and Verma, A. (2002). Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J. Biol. Chem. 277, 23111–23115

    Article  CAS  PubMed  Google Scholar 

  • Majors, B.S., Betenbaugh, M.J., and Chiang, G.G. (2007). Links between metabolism and apoptosis in mammalian cells: applications for anti-apoptosis engineering. Metab. Eng. 9, 317–326.

    Article  CAS  PubMed  Google Scholar 

  • Na, K.S., Park, B.C., Jang, M., Cho, S., Lee, D.H., Kang, S., Lee, C.-K., Bae, K.-H., and Park, S.G. (2007). Protein disulfide isomerase is cleaved by caspase-3 and -7 during apoptosis. Mol. Cells 24, 261–267.

    CAS  PubMed  Google Scholar 

  • Plas, D.R., and Thompson, C.B. (2002). Cell metabolism in the regulation of programmed cell death. Trends Endocrinol. Metab. 13, 75–78.

    Article  PubMed  Google Scholar 

  • Priault, M., Chaudhuri, B., Clow, A., Camougrand, N., and Manon, S. (1999). Investigation of bax-induced release of cytochrome c from yeast mitochondria permeability of mitochondrial membranes, role of VDAC and ATP requirement. Eur. J. Biochem. 260, 684–691.

    Article  CAS  PubMed  Google Scholar 

  • Robey, R.B., and Hay, N. (2006). Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene 25, 4683–4696.

    Article  CAS  PubMed  Google Scholar 

  • Schaefer, U., Boos, W., Takors, R., and Weuster-Botz, D. (1999). Automated sampling device for monitoring intracellular metabolite dynamics. Anal. Biochem. 270, 88–96.

    Article  CAS  PubMed  Google Scholar 

  • Segel, I.H. (1975). Enzyme kinetics, Chapter 7 and 8, (New York: Wiley-Inter-science).

    Google Scholar 

  • Sen, N., Hara, M., Kornberg, M.D., Cascio, M.B., Bae, B.I., Shahani, N., Thomas, B., Dawson, T.M., Dawson, V.L., Snyder, S.H., et al. (2008). Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat. Cell Biol. 10, 866–873.

    Article  CAS  PubMed  Google Scholar 

  • Shim, H.Y., Park, J.H., Paik, H.D., Nah, S.Y., Kim, D.S., and Han Y.S. (2007). Acacetin-induced apoptosis of human breast cancer MCF-7 cells involves caspase cascade, mitochondriamediated death signaling and SAPK/JNK1/2-c-Jun activation. Mol. Cells 24, 95–104.

    CAS  PubMed  Google Scholar 

  • Shimizu, T., Kono, N., Kiyokawa, H., Yamada, Y., Hara, N., Mineo, I., Kawachi, M., Nakajima, H., Wang, Y.L., and Tarui, S. (1998). Erythrocyte glycolysis and its marked alteration by muscular exercise in type VII glycogenosis. Blood 71, 1130–1134.

    Google Scholar 

  • Unwin, R.D., Craven, R.A., Harnden, P., Hanrahan, S., Totty, N., Knowles, M., Eardley, I., Selby, P.J., and Banks, R.E. (2003). Proteomic changes in renal cancer and co-ordinate demonstration of both the glycolytic and mitochondrial aspects of the Warburg effect. Proteomics 3, 1620–1632.

    Article  CAS  PubMed  Google Scholar 

  • Vander Heiden, M.G., Plas, D.R., Rathmell, J.C., Fox, C.J., Harris, M.H., and Thompson, C.B. (2001). Growth factors can influence cell growth and survival though effects on glucose metabolism. Mol. Cell. Biol. 21, 5899–5912.

    Article  Google Scholar 

  • Vazquez, A., de Menezes, M.A., Barabasi, A.-L., and Oltvai, Z.N. (2008). Impact of limited solvent capacity on metabolic rate, enzyme activities, and metabolite concentrations of S. cerevisiae glycolysis. PloS Comp. Biol. 4, e1000195.

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Correspondence to Kwang-Hee Bae or Sung Goo Park.

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These authors contributed equally to this work.

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Jang, M., Kang, H.J., Lee, S.Y. et al. Glyceraldehyde-3-phosphate, a glycolytic intermediate, plays a key role in controlling cell fate via inhibition of caspase activity. Mol Cells 28, 559–563 (2009). https://doi.org/10.1007/s10059-009-0151-7

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  • DOI: https://doi.org/10.1007/s10059-009-0151-7

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