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Thiostrepton, a Natural Compound That Triggers Heat Shock Response and Apoptosis in Human Cancer Cells: A Proteomics Investigation

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Advancements of Mass Spectrometry in Biomedical Research

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 806))

Abstract

Thiostrepton is a natural antibiotic produced by bacteria of Streptomyces genus. We identified Thiostrepton as a strong hit in a cell-based small molecule screen for DIAP1 stability modulators. It was shown previously that Thiostrepton induces upregulation of several gene products in Streptomyces lividans, including the TipAS and TipAL isoforms, and that it can induce apoptotic cell death in human cancer cells. Furthermore, it was suggested that thiostrepton induces oxidative and proteotoxic stress, as inferred from the transcriptional upregulation of stress-related genes and endoplasmic reticulum (ER) stress genes. We used a combination of biochemical and proteomics approaches to investigate the effect of Thiostrepton and other compounds in human cells. Our mass-spectrometry data and subsequent biochemical validation shows that Thiostrepton (and MG-132 proteasome inhibitor) trigger upregulation of heat shock proteins HspA1A, Hsp70, Hsp90α, or Hsp105 in various human cancer cells. We propose a model where Thiostrepton-induced proteasome inhibition leads to accumulation of protein aggregates that trigger a heat shock response and apoptosis in human cancer cells.

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Abbreviations

DIAP1:

Drosophila inhibitor of apoptosis protein 1

DMSO:

Dimethyl sulphoxide

m/z :

Mass/charge

MS:

Mass spectrometry

NAC:

N-acetylcysteine

nanoLC-MS/MS:

Nanoliquid chromatography tandem mass spectrometry

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

WB:

Western blotting

References

  1. Donovick R, Pagano JF, Stout HA, Weinstein MJ (1955) Thiostrepton, a new antibiotic. I. In vitro studies. Antibiot Annu 3:554–559

    Google Scholar 

  2. Dutcher JD, Vandeputte J (1955) Thiostrepton, a new antibiotic. II. Isolation and chemical characterization. Antibiot Annu 3:560–561

    Google Scholar 

  3. Jambor WP, Steinberg BA, Suydam LO (1955) Thiostrepton, a new antibiotic. III. In vivo studies. Antibiot Annu 3:562–565

    Google Scholar 

  4. Ding Z, German P, Bai S, Feng Z, Gao M, Si W, Sobieski MM, Stephan CC, Mills GB, Jonasch E (2012) Agents that stabilize mutated von Hippel-Lindau (VHL) protein: results of a high-throughput screen to identify compounds that modulate VHL proteostasis. J Biomol Screen 17:572–580

    Article  CAS  Google Scholar 

  5. Walsh CT, Acker MG, Bowers AA (2010) Thiazolyl peptide antibiotic biosynthesis: a cascade of post-translational modifications on ribosomal nascent proteins. J Biol Chem 285:27525–27531

    Article  CAS  Google Scholar 

  6. Chiu ML, Folcher M, Griffin P, Holt T, Klatt T, Thompson CJ (1996) Characterization of the covalent binding of thiostrepton to a thiostrepton-induced protein from Streptomyces lividans. Biochemistry 35:2332–2341

    Article  CAS  Google Scholar 

  7. Halasi M, Zhao H, Dahari H, Bhat UG, Gonzalez EB, Lyubimo AV, Tonetti DA, Gartel AL (2010) Thiazole antibiotics against breast cancer. Cell Cycle 9:1214–1217

    Article  CAS  Google Scholar 

  8. Kwok JM, Myatt SS, Marson CM, Coombes RC, Constantinidou D, Lam EW (2008) Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression. Mol Cancer Ther 7:2022–2032

    Article  CAS  Google Scholar 

  9. Bhat UG, Zipfel PA, Tyler DS, Gartel AL (2008) Novel anticancer compounds induce apoptosis in melanoma cells. Cell Cycle 7:1851–1855

    Article  CAS  Google Scholar 

  10. Qiao S, Lamore SD, Cabello CM, Lesson JL, Munoz-Rodriguez JL, Wondrak GT (2012) Thiostrepton is an inducer of oxidative and proteotoxic stress that impairs viability of human melanoma cells but not primary melanocytes. Biochem Pharmacol 83:1229–1240

    Article  CAS  Google Scholar 

  11. Bhat UG, Halasi M, Gartel AL (2009) Thiazole antibiotics target FoxM1 and induce apoptosis in human cancer cells. PLoS One 4:e5592

    Article  Google Scholar 

  12. Newick K, Cunniff B, Preston K, Held P, Arbiser J, Pass H, Mossman B, Shukla A, Heintz N (2012) Peroxiredoxin 3 is a redox-dependent target of thiostrepton in malignant mesothelioma cells. PLoS One 7:e39404

    Article  CAS  Google Scholar 

  13. Radhakrishnan SK, Bhat UG, Hughes DE, Wang IC, Costa RH, Gartel AL (2006) Identification of a chemical inhibitor of the oncogenic transcription factor forkhead box M1. Cancer Res 66:9731–9735

    Article  CAS  Google Scholar 

  14. Hegde NS, Sanders DA, Rodriguez R, Balasubramanian S (2011) The transcription factor FOXM1 is a cellular target of the natural product thiostrepton. Nat Chem 3:725–731

    Article  CAS  Google Scholar 

  15. Bhat UG, Halasi M, Gartel AL (2009) FoxM1 is a general target for proteasome inhibitors. PLoS One 4:e6593

    Article  Google Scholar 

  16. Sandu C, Ryoo HD, Steller H (2010) Drosophila IAP antagonists form multimeric complexes to promote cell death. J Cell Biol 190:1039–1052

    Article  CAS  Google Scholar 

  17. Carrington PE, Sandu C, Wei Y, Hill JM, Morisawa G, Huang T, Gavathiotis E, Werner MH (2006) The structure of FADD and its mode of interaction with procaspase-8. Mol Cell 22:599–610

    Article  CAS  Google Scholar 

  18. Woods AG, Sokolowska I, Darie CC (2012) Identification of consistent alkylation of cysteine-less peptides in a proteomics experiment. Biochem Biophys Res Commun 419:305–308

    Article  CAS  Google Scholar 

  19. Sokolowska I, Gawinowicz MA, Ngounou Wetie AG, Darie CC (2012) Disulfide proteomics for identification of extracellular or secreted proteins. Electrophoresis 33:2527–2536

    Article  CAS  Google Scholar 

  20. Sokolowska I, Woods AG, Gawinowicz MA, Roy U, Darie CC (2012) Identification of a potential tumor differentiation factor receptor candidate in prostate cancer cells. FEBS J 279:2579–2594

    Article  CAS  Google Scholar 

  21. Darie CC, Deinhardt K, Zhang G, Cardasis HS, Chao MV, Neubert TA (2011) Identifying transient protein-protein interactions in EphB2 signaling by blue native PAGE and mass spectrometry. Proteomics 11:4514–4528

    Article  CAS  Google Scholar 

  22. Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC (1994) Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371:346–347

    Article  CAS  Google Scholar 

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Acknowledgements

H. Steller is an Investigator of the Howard Hughes Medical Institute. Part of this work was supported by NIH grant R01GM60124 to H.S. and a grant from Melanoma Research Alliance. Part of this work was supported by the U.S. Army Research Office through the Defense University Research Instrumentation Program (DURIP grant #W911NF-11-1-0304) to CCD. C.S. thanks Jerry Chipuk (The Mount Sinai Hospital, NY) for the kind gift of MeWo cell line. CS and CCD thank Dr. Alisa G. Woods (Clarkson University) for discussions regarding the manuscript.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Strang Laboratory of Apoptosis and Cancer Biology, The Rockefeller University, New York, NY, 10065, USA

    Cristinel Sandu & Hermann Steller

  2. Biochemistry and Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, NY, 13699, USA

    Armand G. Ngounou Wetie & Costel C. Darie

Authors
  1. Cristinel Sandu
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  2. Armand G. Ngounou Wetie
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  3. Costel C. Darie
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  4. Hermann Steller
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Corresponding author

Correspondence to Hermann Steller .

Editor information

Editors and Affiliations

  1. Chemistry and Biomolecular Science Biochemistry and Proteomics Group, Clarkson University, Potsdam, New York, USA

    Alisa G. Woods

  2. Chemistry and Biomolecular Science Biochemistry and Proteomics Group, Clarkson University, Potsdam, New York, USA

    Costel C. Darie

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© 2014 Springer International Publishing Switzerland

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Sandu, C., Wetie, A.G.N., Darie, C.C., Steller, H. (2014). Thiostrepton, a Natural Compound That Triggers Heat Shock Response and Apoptosis in Human Cancer Cells: A Proteomics Investigation. In: Woods, A., Darie, C. (eds) Advancements of Mass Spectrometry in Biomedical Research. Advances in Experimental Medicine and Biology, vol 806. Springer, Cham. https://doi.org/10.1007/978-3-319-06068-2_21

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