Skip to main content

Advertisement

SpringerLink
Log in

Inhibition of Heat Shock Protein Response Enhances PS-341-Mediated Glioma Cell Death

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Previous study indicated that PS-341 induces cell death via JNK pathway in vitro in glioma. However, suppressing proteasome complex by PS-341 may induce expression of heat shock proteins (HSPs), which confer potential protection against cellular stress. In this study, we explored whether induction of HSPs could impair PS-341-induced cell death and whether inhibition of HSPs could enhance cell damage induced by PS-341 in glioma cells.

Methods

HSP expression in glioma cells was modulated by HSP inhibitor, sublethal heat, or knockdown of heat shock factor1 (HSF1), then PS-341-induced cell damage was examined by different methods. Similar experiments were also performed in HSF1+/+ and HSF1–/– cells. HSP70 expression and HSF1 nuclear localization were compared between glioma and normal brain tissues.

Results

HSP level was upregulated mediated by HSF1 when glioma cells were treated with PS-341. PS-341-mediated cell damage could be significantly augmented by HSP inhibition. Furthermore, HSP70 expression and HSF1 nuclear localization were much more abundant in gliomas than in normal brain tissues.

Conclusions

Our results demonstrated that HSP70 impaired cell death induced by PS-341 in glioma cells. Administration of PS-341 in combination with either HSP70 inhibitor or HSF1 knockdown may act as a new approach to treatment of glioma.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Nishikawa R (2010) Standard therapy for glioblastoma–a review of where we are. Neurol Med Chir (Tokyo) 50(9):713–9.

    Article  Google Scholar 

  2. Stupp R, Hegi ME, et al. (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–66.

    Article  PubMed  CAS  Google Scholar 

  3. Stupp R, Mason WP, et al. (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–96.

    Article  PubMed  CAS  Google Scholar 

  4. Fulda S, Wick W, et al. (2002) Smac agonists sensitize for Apo2L/TRAIL-or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8(8):808–15.

    PubMed  CAS  Google Scholar 

  5. Demartino GN, Gillette TG (2007) Proteasomes: machines for all reasons. Cell 129(4):659–62.

    Article  PubMed  CAS  Google Scholar 

  6. Almond JB, Cohen GM (2002) The proteasome: a novel target for cancer chemotherapy. Leukemia 16(4):433–43.

    Article  PubMed  CAS  Google Scholar 

  7. Adams J (2002) Proteasome inhibitors as new anticancer drugs. Curr Opin Oncol 14(6):628–34.

    Article  PubMed  CAS  Google Scholar 

  8. Yang Y, Kitagaki J, et al. (2009) Targeting the ubiquitin-proteasome system for cancer therapy. Cancer Sci 100(1):24–8.

    Article  PubMed  CAS  Google Scholar 

  9. Adams J (2002) Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment of cancer. Curr Opin Chem Biol 6(4):493–500.

    Article  PubMed  CAS  Google Scholar 

  10. Adams J, Palombella VJ, et al. (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59(11):2615–22.

    PubMed  CAS  Google Scholar 

  11. Ling YH, Liebes L, et al. (2003) Mechanisms of proteasome inhibitor PS-341-induced G(2)-M-phase arrest and apoptosis in human non-small cell lung cancer cell lines. Clin Cancer Res 9(3):1145–54.

    PubMed  CAS  Google Scholar 

  12. Yeung BH, Huang DC, et al. (2006) PS-341 (bortezomib) induces lysosomal cathepsin B release and a caspase-2-dependent mitochondrial permeabilization and apoptosis in human pancreatic cancer cells. J Biol Chem 281(17):11923–32.

    Article  PubMed  CAS  Google Scholar 

  13. Nawrocki ST, Bruns CJ, et al. (2002) Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther 1(14):1243–53.

    PubMed  CAS  Google Scholar 

  14. Yin D, Zhou H, et al. (2005) Proteasome inhibitor PS-341 causes cell growth arrest and apoptosis in human glioblastoma multiforme (GBM). Oncogene 24(3):344–54.

    Article  PubMed  CAS  Google Scholar 

  15. Bross PF, Kane R, et al. (2004) Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res 10(12 Pt 1):3954–64.

    Article  PubMed  CAS  Google Scholar 

  16. Phuphanich S, Supko JG, et al. (2010) Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma. J Neurooncol 100(1):95–103.

    Article  PubMed  CAS  Google Scholar 

  17. Roue G, Perez-Galan P, et al. (2011) The Hsp90 inhibitor IPI-504 overcomes bortezomib resistance in mantle cell lymphoma in vitro and in vivo by down-regulation of the prosurvival ER chaperone BiP/Grp78. Blood 117(4):1270–9.

    Article  PubMed  CAS  Google Scholar 

  18. Hayashi S, Yamamoto M, et al. (2001) Expression of nuclear factor-kappa B, tumor necrosis factor receptor type 1, and c-Myc in human astrocytomas. Neurol Med Chir (Tokyo) 41(4):187–95.

    Article  CAS  Google Scholar 

  19. Koschny R, Holland H, et al. (2007) Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Clin Cancer Res 13(11):3403–12.

    Article  PubMed  CAS  Google Scholar 

  20. Tianhu Z, Shiguang Z, et al. (2010) Bmf is upregulated by PS-341-mediated cell death of glioma cells through JNK phosphorylation. Mol Biol Rep 37(3):1211–9.

    Article  PubMed  Google Scholar 

  21. Mitsiades N, Mitsiades CS, et al. (2002) Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci USA 99(22):14374–9.

    Article  PubMed  CAS  Google Scholar 

  22. Morimoto RI, Kline MP, et al. (1997) The heat-shock response: regulation and function of heat-shock proteins and molecular chaperones. Essays Biochem 32:17–29.

    PubMed  CAS  Google Scholar 

  23. Koishi M, Yokota S, et al. (2001) The effects of KNK437, a novel inhibitor of heat shock protein synthesis, on the acquisition of thermotolerance in a murine transplantable tumor in vivo. Clin Cancer Res 7(1):215–9.

    PubMed  CAS  Google Scholar 

  24. Drexler HC (1997) Activation of the cell death program by inhibition of proteasome function. Proc Natl Acad Sci USA 94(3):855–60.

    Article  PubMed  CAS  Google Scholar 

  25. Masdehors P, Omura S, Merle-Béral H, et al. (1999) Increased sensitivity of CLL-derived lymphocytes to apoptotic death activation by the proteasome-specific inhibitor lactacystin. Br J Haematol 105(3):752–7.

    Article  PubMed  CAS  Google Scholar 

  26. Richardson PG, Mitsiades C (2005) Bortezomib: proteasome inhibition as an effective anticancer therapy. Future Oncol 1(2):161–71.

    Article  PubMed  CAS  Google Scholar 

  27. Badros A, Burger AM, et al. (2009) Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 15(16):5250–7.

    Article  PubMed  CAS  Google Scholar 

  28. Saha MN, Jiang H, et al. (2010) MDM2 antagonist nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity. Cancer Biol Ther 9(11):936–44.

    Article  PubMed  CAS  Google Scholar 

  29. Meister S, Frey B, et al. (2010) Calcium channel blocker verapamil enhances endoplasmic reticulum stress and cell death induced by proteasome inhibition in myeloma cells. Neoplasia 12(7):550–61.

    PubMed  CAS  Google Scholar 

  30. Young JT, Heikkila JJ (2010) Proteasome inhibition induces hsp30 and hsp70 gene expression as well as the acquisition of thermotolerance in Xenopus laevis A6 cells. Cell Stress Chaperones 15(3):323–34.

    Article  PubMed  CAS  Google Scholar 

  31. Sarkozi R, Perco P, et al. (2008) Bortezomib-induced survival signals and genes in human proximal tubular cells. J Pharmacol Exp Ther 327(3):645–56.

    Article  PubMed  Google Scholar 

  32. Park HS, Lee JS, et al. (2001) Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. EMBO J 20(3):446–56.

    Article  PubMed  CAS  Google Scholar 

  33. Meriin AB, Yaglom JA, et al. (1999) Protein-damaging stresses activate c-Jun N-terminal kinase via inhibition of its dephosphorylation: a novel pathway controlled by HSP72. Mol Cell Biol 19(4):2547–55.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was supported by National Natural Science Foundations of China (30901533 to LY and 30973078 to ZS) and Science Foundation for Youth Scholars of Ministry of Education of China (20102307120001 to LY).

Conflict of interest

This study has no commercial interests. No financial or material support was received from any commercial source directly or indirectly related to the scientific work.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, The People’s Republic of China

    Yaohua Liu MD, PhD, Shiguang Zhao MD, PhD, Huailei Liu MD, Dayong Han MD, Yunbo Zhen MD, PhD, Dongxiao Xu MD, Yu Wang MD, Hongyu Yang MD, Guang Zhang MD, Chunlei Wang MD, Jianing Wu MD & Yuanzhu Ye MD

  2. Department of Biochemistry, Harbin Medical University, Harbin, Heilongjiang, The People’s Republic of China

    Tianhu Zheng PhD

Authors
  1. Yaohua Liu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tianhu Zheng PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shiguang Zhao MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huailei Liu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dayong Han MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yunbo Zhen MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dongxiao Xu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu Wang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hongyu Yang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Guang Zhang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chunlei Wang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jianing Wu MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yuanzhu Ye MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shiguang Zhao MD, PhD.

Additional information

Yaohua Liu, Tianhu Zheng and Shiguang Zhao contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, Y., Zheng, T., Zhao, S. et al. Inhibition of Heat Shock Protein Response Enhances PS-341-Mediated Glioma Cell Death. Ann Surg Oncol 19 (Suppl 3), 421–429 (2012). https://doi.org/10.1245/s10434-011-1881-2

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-011-1881-2

Keywords

Search

Navigation