Skip to main content

Advertisement

SpringerLink
Log in

Cytostatic Effect of the Hypothalamic Cytokine PRP-1 is Mediated by mTOR and cMyc Inhibition in High Grade Chondrosarcoma

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

This study aimed to further elucidate the molecular mechanisms of antiproliferative action of proline rich polypeptide 1 (PRP-1) cytokine, produced by neurosecretory cells of the hypothalamus to be considered as alternative adjuvant therapy for metastatic chondrosarcoma, which does not respond to chemotherapy or radiation and currently without any effective treatment. Rapid cell proliferation assay of human primary cultures from high grade chondrosarcoma patients biopsies and human chondrosarcoma JJ012 cell line indicated 50 and 80% inhibition in PRP-1 treated samples correspondingly. Videomicroscopy detected that despite the treatment there are still dividing cells, meaning that cells are not in the state of dormancy, rather PRP-1 repressed the cell cycle progression, exhibited cytostatic effect. The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase that has a crucial role in a nutrient sensitive signaling pathway that regulates cell growth. Experiments with mTOR pathway after PRP-1 (10 μg/ml) treatment indicated statistically significant 30% inhibition of mTOR activity and its 56% inhibition in immunoprecipitates with PRP-1 concentrations effective for cell proliferation inhibition. Treatment with PRP- caused inhibition of mTOR and downstream target cMyc oncogenic transcription factor sufficient to trigger the cytostatic effect in high grade, but not in low grade chondrosarcomas. The fact that lower concentrations than 10 μg/ml peptide with cytostatic effect did not inhibit mTOR, but inhibited cMyc prompted us to assume that PRP-1 binds to two different receptors facilitating the antiproliferative effect.

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. Galoyan AA (2004) Brain neurosecretory cytokines: immune response and neuronal survival. Kluwer Academic/Plenum Publishers, NY

    Google Scholar 

  2. Galoyan A (2008) In: Lajtha A (ed) Handbook of neurochemistry and neurobiology, vol: neuroimmunology (Galoyan A, Besedovsky H (eds)). Springer, New York, pp 155–196

  3. Galoyan AA, Grigorian SL, Badalyan CV (2006) Treatment and prophylaxis of anthrax by brain neurosecretory cytokines. Neurochem Res 31(6):795–803

    Article  PubMed  CAS  Google Scholar 

  4. Galoyan AA, Sarkissian JS, Chavushyan VA et al (2005) Neuroprotective action of hypothalamic peptide PRP-1 at various time survival following spinal cord hemisection. Neurochem Res 30(4):507–525

    Article  PubMed  CAS  Google Scholar 

  5. Galoyan AA (2000) Neurochemistry of brain neuroendocrine immune system: signal molecules. Neurochem Res 25(9/10):1343–1355

    Article  PubMed  CAS  Google Scholar 

  6. Galoyan AA, Aprikyan VS (2002) A new hypothalamic polypeptide is a regulator of myelopoiesis. Neurochem Res 27(4):305–312

    Article  PubMed  CAS  Google Scholar 

  7. Galoyan AA, Shakhlamov VA, Kondakova LI, Altukhova VI, Polyakova GP (2001) The influence of proline-rich polypeptide on the morphology and mitotic activity of neurinoma Hassel node of tumor cells at rats (electron microscopic investigations). PNAS (Russian Academy of Sciences) 101(2):279–286

    Google Scholar 

  8. Galoyan AA, Shakhlamov VA, Malaytsev VV (2001) Changes in tumor cells L929 under PRP effect in vitro. Med Sci Armenia 41(1):25–29

    Google Scholar 

  9. Galoyan AA, Margaryan KS, Hovhannisyan GG, GasparyanD GH, Aroutiounian N, Aroutiounian RM (2009) Study of the genotoxic effects of a Proline-RichPolypeptide using the comet assay. Neurochem J 3(2):145–148

    Article  Google Scholar 

  10. Aroutiounian RM, Hovhannisyan GG, Gasparyan GH, Margaryan KS, Aroutiounian DN, Sarkissyan NK, Galoyan AA (2010) Proline-rich polypeptide-1 protects the cells in vitro from genotoxic effects of mitomycin C. Neurochem Res 35(4):598–6022

    Article  PubMed  CAS  Google Scholar 

  11. Chailakhyan RK, Gerasimov YV, Chailakhyan MR, Galoyan AA (2010) Proline- rich hypothalamic polypeptide has opposite effects on the proliferation of human normal bone marrow stromal cells and human giant-cell tumour stromal cells. Neurochem Res 35(6):934–939

    Article  PubMed  CAS  Google Scholar 

  12. Galoian K, Scully S, McNamara G, Flynn P, Galoyan A (2009) Antitumorigenic effect of brain proline rich polypeptide-1 in human chondrosarcoma. Neurochem Res 34(12):2117–2121

    Article  PubMed  CAS  Google Scholar 

  13. Galoian K, Scully S, Galoyan A (2009) Myc-oncogene inactivating effect by proline rich polypeptide (PRP-1) in chondrosarcoma JJ012 cells. Neurochem Res 34(2):379–385

    Article  PubMed  CAS  Google Scholar 

  14. Schantz JT (2009) Manual in biomedical research, v (Manual for Primary Human Cell cultures. World Scientific Publishing Co Pte Ltd

  15. Freshney R (1987) Culture of animal cells: a manual of basic technique (1987) Alan R. Liss, Inc

  16. Kaelin WG Jr, Thompson CB (2010) Clues from cell metabolism. Nature 465(3):562–564

    Article  PubMed  CAS  Google Scholar 

  17. Barrios C, Castresana JS, Kreicbergs A (1994) Clinicopathologic correlations and short-term prognosis in musculoskeletal sarcoma with c-myc oncogene amplification. Am J Clin Oncol 17:273–276

    Article  PubMed  CAS  Google Scholar 

  18. Morrison C, Radmacher M, Mohammed N, Susterm D, Auer H, Jones S, Riggenbach J, Kelbick N, Bos G, Mayerson J (2005) MYC amplification and polysomy 8 in chondrosarcoma: array comparative genopmic hybridization, fluorescent in situ hybridization, and association with outcome. J Clin Oncol 23(36):9369–9376

    Article  PubMed  CAS  Google Scholar 

  19. Hermeking Heiko (2003) The Myc oncogene as a cancer drug target. Curr Cancer Drug Targets 3:163–175

    Article  PubMed  CAS  Google Scholar 

  20. Felsher DW, Bradon Nicole (2003) Pharmacological Inactivation of MYC for the treatment of cancer. Drug News Perspect 16(6):370–374

    Article  PubMed  CAS  Google Scholar 

  21. Berns EM, Klijn JG, van Putten WL, van Staveren IL, Portengen H, Foekens JA (1992) c-myc amplification is a better prognostic factor than HER2/neu amplification in primary breast cancer. Cancer Res 52:1107–1113

    PubMed  CAS  Google Scholar 

  22. Shaw RJ (2006) Glucose metabolism and cancer. Curr Opin Cell Biol 18(6):598–608

    Article  PubMed  CAS  Google Scholar 

  23. Rosenwald IB, Kaspar R, Rousseau D, Gehrke L, Leboulch P, Chen JJ, Schmidt EV, Sonenberg N, London IM (1995) Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J Biol Chem 270(36):21176–21180

    Article  PubMed  CAS  Google Scholar 

  24. Nelsen CJ, Rickheim DG, Tucker MM, Hansen LK, Albrecht JH (2003) Evidence that cyclin D1 mediates both growth and proliferation downstream of TOR in hepatocytes. J Biol Chem 278(6):3656–3663

    Article  PubMed  CAS  Google Scholar 

  25. Richter JD, Sonenberg N (2005) Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433:477–480

    Article  PubMed  CAS  Google Scholar 

  26. Schmidt EV (2004) The role of c-myc in regulation of translation initiation. Oncogene 23:3217–3221

    Article  PubMed  CAS  Google Scholar 

  27. Curtis BM, Widmer MB, de Roos P, Qwarnstrom EE (1990) IL-1 and its receptor are translocated to the nucleus. J Immunol 144(4):1295–1303

    PubMed  CAS  Google Scholar 

  28. Subramaniam PS, Green MM, Larkin J III, Torres BA, Johnson HM (2001) Nuclear Translocation of IFN-g Is an intrinsic requirement for its biologic activity and can be driven by a heterologous nuclear localization sequence. J Interferon Cytokine Res 21:951–959

    Article  PubMed  CAS  Google Scholar 

  29. Korn EL, Arbuck SG, Pluda JM, Simon R, Kaplan RS, Christian MC (2001) Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol 19(1):265–272

    PubMed  CAS  Google Scholar 

  30. Pasquier E, Carré M, Pourroy B, Camoin L, Rebaï O, Briand C, Braguer D (2004) Antiangiogenic activity of paclitaxel is associated with its cytostatic effect, mediated by the initiation but not completion of a mitochondrial apoptotic signaling pathway. Mol Cancer Ther 3(10):1301–1310

    PubMed  CAS  Google Scholar 

  31. Edward LK, Susan GA, James MP, Richard S, Richard SK, Michaele CC (2001). Clinical trial designs for cytostatic agents: are new approaches needed. J Clin Oncol 19(1):265–272

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopedics, UHealth, Miller School of Medicine, University of Miami, 1600 NW 10th Ave, Suite 8006 (r-2), Miami, FL, 33136, USA

    Karina Galoian

  2. Department of Orthopedics, UHealth, Miller School of Medicine, University of Miami, 1400 NW 12 Ave, r. 4036, Miami, FL, 33136, USA

    Thomas H. Temple

  3. Institute of Biochemistry, National Academy of Sciences, 5/1 Paruir Sevak Str., Yerevan, 0014, Republic of Armenia

    Armen Galoyan

Authors
  1. Karina Galoian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas H. Temple
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Armen Galoyan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karina Galoian.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Galoian, K., Temple, T.H. & Galoyan, A. Cytostatic Effect of the Hypothalamic Cytokine PRP-1 is Mediated by mTOR and cMyc Inhibition in High Grade Chondrosarcoma. Neurochem Res 36, 812–818 (2011). https://doi.org/10.1007/s11064-011-0406-5

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-011-0406-5

Keywords

Search

Navigation