Skip to main content
SpringerLink
Log in

Anti-apoptotic actions of cycloheximide: blockade of programmed cell death or induction of programmed cell life?

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Cycloheximide (CHX), long recognized for its ability to inhibit protein synthesis, has been widely employed in studies of cell death to the extent that prevention of cell death by CHX has been used as prima facie evidence for a subtype of apoptosis called ‘programmed cell death’. However, very rarely have investigators determined the effects of CHX on protein synthesis in their particular cell death paradigms. Recent findings are revealing alternative mechanisms of action of CHX that involve, ironically, stimulation of cytoprotective signalling pathways. For example, in embryonic rat hippocampal cell cultures CHX protects neurons against oxidative insults by a mechanism involving induction of neuroprotective gene products including Bcl-2. CHX induces increases in immediate early gene mRNA levels, and can activate several different kinases and transcription factors that are also activated by various insults and in response to anti-apoptotic growth factors. Concentrations of CHX that cause only a modest and/or transient decrease in over-all protein synthesis may prevent cell death by inducing cytoprotective signalling pathways (‘programmed cell life’), whereas higher concentrations of CHX may prevent cell death by blocking the expression of ‘death genes’. Establishing which of these anti-apoptotic mechanisms of action of CHX is operative in each cell death paradigm is clearly essential for proper interpretation of experimental results.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Du C, Hu R, Csernansky CA, Hsu CY, Choi DW. Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis? J Cereb Blood Flow Metab 1996; 16: 195-201.

    Google Scholar 

  2. Ciutat D, Esquerda JE, Caldero J. Evidence for calcium regulation of spinal cord motorneuron death in the chick embryo in vivo. Dev Brain Res 1995; 86: 167-179.

    Google Scholar 

  3. Kobayashi T, Tominaga T, Yoshimoto T. Cell death due to ACNU-induced DNA fragmentation: inhibition by cycloheximide. J Neurooncol 1994; 22: 23-31.

    Google Scholar 

  4. Wyllie AH, Martin RG, Smith AL, Dunlop D. Chromatin cleavage in apoptosis: association with condensed chromatin morphology and dependence on macromolecular synthesis. J Pathol 1984; 142: 67-77.

    Google Scholar 

  5. Martin DP, Schmidt RE, DiStefano PS, Lowry OH, Carter JG, Johnson EM Jr. Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation. J Cell Biol 1988; 106: 829-844.

    Google Scholar 

  6. Scott SA, Davies AM. Inhibition of protein synthesis prevents cell death in sensory and parasympathetic neurons deprived of neurotrophic factor in vitro. J Neurobiol 1990; 21: 630-638.

    Google Scholar 

  7. Oppenheim RW, Prevette D, Tytell M, Homma S. Naturally occurring and induced neuronal death in the chick embryo in vivo requires protein and RNA synthesis: evidence for the role of cell death genes. Dev Biol 1990; 138: 104-113.

    Google Scholar 

  8. Rehen SK, Vareita MH, Freitas FG, Morses MO, Linden R. Contrasting effects of protein synthesis inhibition and of cyclic AMP on apoptosis in the developing retina. Development 1996; 122: 1438-1448.

    Google Scholar 

  9. Furukawa K, Estus S, Fu W, Mark RJ, Mattson MP. Neuroprotective action of cycloheximide involves induction of Bcl-2 and antioxidant pathways. J Cell Biol 1997; 136: 1137-1150.

    Google Scholar 

  10. Yonish-Rouach E, Deguin V, Zaitchouk T, et al. Transcriptional activation plays a role in the induction of apoptosis by transiently transfected wild-type p53. Oncogene 1995; 11: 2197-2205.

    Google Scholar 

  11. Schulz JB, Weller M, Klockgether T. Potassium deprivation-induced apoptosis of cerebellar granule neurons: a sequential requirement for new mRNA and protein synthesis, ICE-like protease activity, and reactive oxygen species. J Neurosci 1996; 16: 4696-4706.

    Google Scholar 

  12. Horvitz HR, Shaham S, Hengartner MO. The genetics of programmed cell death in the nematode Caenorhabditis elegans. Cold Spring Harb Symp Quant Biol 1994; 59: 377-385.

    Google Scholar 

  13. Villa P, Miehe M, Sensenbrenner M, Pettmann B. Synthesis of specific proteins in trophic factor-deprived neurons undergoing apoptosis. J Neurochem 1994; 62: 1468-1475.

    Google Scholar 

  14. Loo DT, Copani A, Pike CJ, Whittemore ER, Walencewicz AJ, Cotman CW. Apoptosis is induced by β-amyloid in cultured central nervous system neurons. Proc Natl Acad Sci USA 1993; 90: 7951-7955.

    Google Scholar 

  15. Mattson MP, Furukawa K. Programmed cell life: anti-apoptotic signaling and therapeutic strategies for neurodegenerative disorders. Retorative Neurol Neurosci 1996; 9: 191-205.

    Google Scholar 

  16. Okuda A, Matsuzaki A, Kimura G. Transient increase in the c-fos mRNA level after change of culture condition from serum absence to serum presence and after cycloheximide addition in rat 3Y1 fibroblasts. Biochem Biophys Res Commun 1989; 159: 501-507.

    Google Scholar 

  17. Edwards DR, Mahadevan LC. Protein synthesis inhibitors differentially superinduce c-fos and c-jun by three distinct mechanisms: lack of evidence for labile repressors. EMBO J 1992; 11: 2415-2424.

    Google Scholar 

  18. Penhoat A, Jaillard C, Begeot M, Durand P, Saez JM. Cycloheximide enhances ACTH-receptor mRNA through transcriptional and post-transcriptional mechanisms in bovine adrenocortical cells. Mol Cell Endocrinol 1996; 121: 57-63.

    Google Scholar 

  19. Zinck R, Cahill MA, Kracht M, Sachsenmaier C, Hipskind RA, Nordheim A. Protein synthesis inhibitors reveal differential regulation of mitogen-activated protein kinase and stress-activated protein kinase pathways that converge on Elk-1. Mol Cell Biol 1995; 15: 4930-4938.

    Google Scholar 

  20. Gardner AM, Johnson GL. Fibroblast growth factor-2 suppression of tumor necrosis factor α-mediated apoptosis requires Ras and the activation of mitogen-activated protein kinase. J Biol Chem 1996; 271: 14560-14566.

    Google Scholar 

  21. Nishina H, Fischer KD, Radvanyi L, et al. Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3. Nature 1997; 385: 350-353.

    Google Scholar 

  22. Kimura K, Yamamoto M. Modification of the alternative splicing process of testosterone-repressed prostate message-2 (TRPM-2) gene by protein synthesis inhibitors and heat shock treatment. Biochim Biophys Acta 1996; 1307: 83-88.

    Google Scholar 

  23. Carter DA. Up-regulation of β1-adrenoceptor messenger ribonucleic acid in the rat pineal gland: nocturnally, through a β-adrenoceptor-linked mechanism, and in vitro, through a novel posttranscriptional mechanism activated by specific protein synthesis inhibitors. Endocrinology 1993; 133: 2263-2268.

    Google Scholar 

  24. Ledda-Columbano GM, Coni P, Faa P, Manenti G, Columbano A. Rapid induction of apoptosis in rat liver by cycloheximide. Am J Pathol 1992; 140: 545-549.

    Google Scholar 

  25. Ishii HH, Etheridge MR, Gobe GC. Cycloheximide-induced apoptosis in Burkitt lymphoma (BJA-B) cells with and without Epstein-Barr virus infection. Immunol Cell Biol 1995; 73: 463-468.

    Google Scholar 

  26. Millar CG, Baxter GF, Thiemermann C. Protection of the myocardium by ischaemic preconditioning: mechanisms and therapeutic implications. Pharmacol Ther 1996; 69: 143-151.

    Google Scholar 

  27. Wong HR, Mannix RJ, Rusnak JM, et al. The heat-shock response attenuates lipopolysaccharide-mediated apoptosis in cultured sheep pulmonary artery endothelial cells. Am J Respir Cell Mol Biol 1996; 15: 745-751.

    Google Scholar 

  28. Barger SW, Mattson MP. Excitatory amino acids and growth factors: biological and molecular interactions regulating neuronal survival and plasticity. In: CNS Neurotransmitters and Neuromodulators Vol. 2. Boca Raton, FL (USA): CRC Press, 1995: 273-294.

    Google Scholar 

  29. Mattson MP. Free radicals, calcium, and the synaptic plasticity — cell death continuum: emerging roles of the transcription factor NFκB. 1997; Int Rev Neurobiol (in press.)

  30. Cheng B, Christakos S, Mattson MP. Tumor necrosis factors protect neurons against excitotoxic/metabolic insults and promote maintenance of calcium homeostasis. Neuron 1994; 12: 139-153.

    Google Scholar 

  31. Barger SW, Horster D, Furukawa K, Goodman Y, Krieglstein J, Mattson MP. Tumor necrosis factors α and β protect neurons against amyloid β-peptide toxicity: evidence for involvement of a κB-binding factor and attenuation of peroxide and Ca2+ accumulation. Proc Natl Acad Sci USA 1995; 92: 9328-9332.

    Google Scholar 

  32. Barger SW, Mattson MP. Induction of neuroprotective κB-dependent transcription by secreted forms of the Alzheimer's β-amyloid precursor. Mol Brain Res 1995; 40: 116-126.

    Google Scholar 

  33. Bruce AJ, Boling W, Kindy MS, et al. Altered neuronal and microglial responses to brain injury in mice lacking TNF receptors. Nature Medicine 1996; 2: 788-794.

    Google Scholar 

  34. Menegazzi M, Guerriero C, Carcereri de Prati A, Cardinale C, Suzuki H, Armato U. TPA and cycloheximide modulate the activation of NF-κB and the induction and stability of nitric oxide synthase transcript in primary neonatal rat hepatocytes. FEBS Lett 1996; 379: 279-285.

    Google Scholar 

  35. Morris EJ, Geller HM. Induction of neuronal apoptosis by camptothecin, an inhibitor of DNA topoisomerase-1: evidence for cell cycle-independent toxicity. J Cell Biol 1996; 134: 757-770.

    Google Scholar 

  36. Goto K, Ishige A, Sekiguchi K, Iizuka S, Sugimoto A, Yuzurihara M. Effects of cycloheximide on delayed neuornal death in rat hippocampus. Brain Res 1990; 534: 299-302.

    Google Scholar 

  37. Linnik MD, Zobrist RH, Hatfield MD. Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Stroke 1993; 24: 2002-2008.

    Google Scholar 

  38. MacManus JP, Buchan AM, Hill IE, Rasquinha I, Preston E. Global ischemia can cause DNA fragmentation indicative of apoptosis in rat brain. Neurosci Lett 1993; 164: 89-92.

    Google Scholar 

  39. Svendsen CN, Kew JN, Staley K, Sofroniew MV. Death of developing septal cholinergic neurons following NGF withdrawal in vitro: protection by protein synthesis inhibition. J Neurosci 1994; 14: 75-87.

    Google Scholar 

  40. Tortosa A, Rivera R, Ferrer I. Dose-related effects of cycloheximide on delayed neuronal death in the gerbil hippocampus after bilateral transitory forebrain ischemia. J Neurol Sci 1994; 121: 10-17.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA

    M. P. Mattson & K. Furukawa

Authors
  1. M. P. Mattson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Furukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mattson, M.P., Furukawa, K. Anti-apoptotic actions of cycloheximide: blockade of programmed cell death or induction of programmed cell life?. Apoptosis 2, 257–264 (1997). https://doi.org/10.1023/A:1026433019210

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026433019210

Search

Navigation