Skip to main content
Log in

Role of dephosphorylation of FOXO1 on apoptosis induced by wortmannin for non-Hodgkin’s lymphoma cells

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

The aim of this study was to ascertain the relationship between the phosphorylation of FOXO1 and the apoptosis and the proliferation of lymphoma cells so as to further clarify the cellular biology and pathogenesis of the disease. The lymphoma cells Namalwa and Jurkat were treated with PI3K inhibitor wortmannin or etoposide alone or wortmannin plus etoposide with different schedule. The inhibition rates of lymphoma cell growth were examined by XTT assay. Apoptosis were detected by flow cytometry. The expression of p-Akt, p-FOXO1, FOXO1, bim were determined by western blot analysis. Wortmannin induced apoptosis of Jurkat cells and Namalwa cells and inhibited their survival effectively. The rate of growth inhibition and apoptosis of lymphoma cells induced by wortmannin plus etoposide were higher than those induced by etoposide alone. After treated with wortmannin, phosphorylation of FOXO1 remarkably reduced and bim increased. The dephosphorylation of FOXO1 inhibited proliferation of Jurkat cells and Namalwa cells, promoted their apoptosis and sensitized Non-Hodgkin lymphoma cells to etoposide. Bim activated by FOXO1 promoted cells apoptosis.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Roeb W, Boyer A, Cavenee WK, Arden KC (2008) Guilt by association: PAX3-FOXO1 regulates gene expression through selective destabilization of the EGR1 transcription factor. Cell Cycle 7:837–841

    CAS  PubMed  Google Scholar 

  2. Xia SJ, Barr FG (2005) Chromosome translocations in sarcomas and the emergence of oncogenic transcription factors. Eur J Cancer 41:2513–2527

    CAS  PubMed  Google Scholar 

  3. Paik JH, Kollipara R, Chu G et al (2007) FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128:309–323

    Article  CAS  PubMed  Google Scholar 

  4. Ciechomska I, Pyrzynska B, Kazmierczak P, Kaminska B (2003) Inhibition of Akt kinase signalling and activation of Forkhead are indispensable for upregulation of FasL expression in apoptosis of glioma cells. Oncogene 22:7617–7627

    Article  CAS  PubMed  Google Scholar 

  5. Lentzsch S, Chatterjee M, Gries M, Bommert K, Gollasch H, Dörken B, Bargou RC (2004) PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells. Leukemia 18:1883–1890

    Article  CAS  PubMed  Google Scholar 

  6. Sourbier C, Lindner V, Lang H et al (2006) The phosphoinositide 3-kinase/Akt pathway: a new target in human renal cell carcinoma therapy. Cancer Res 66:5130–5142

    Article  CAS  PubMed  Google Scholar 

  7. Amstutz R, Wachtel M, Troxler H et al (2008) Phosphorylation regulates transcriptional activity of PAX3/FKHR and reveals novel therapeutic possibilities. Cancer Res 68:3767–3776

    Article  CAS  PubMed  Google Scholar 

  8. Burgering BMT, Medema RH (2003) Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. Leukoc Biol 75:1–13

    Article  Google Scholar 

  9. Lynch DK, Ellis CA, Edwards PA, Hiles ID (1999) Integrin-linked kinase regulates phosphorylation of serine473 of protein kinase B by an indirect mechanism. Oncogene 18:8024–8032

    Article  CAS  PubMed  Google Scholar 

  10. Jia L, Yu W, Wang P, Sanders BG, Kline K (2008) In vivo and in vitro studies of anticancer actions of alpha-TEA for human prostate cancer cells. Prostat 68:849–860

    Article  CAS  Google Scholar 

  11. Adachi M, Osawa Y, Uchinami H, Kitamura T, Accili D, Brenner DA (2007) The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells. Gastroenterology 132:1434–1446

    Article  CAS  PubMed  Google Scholar 

  12. Yan L, Lavin VA, Moser LR, Cui Q, Kanies C, Yang (2008) PP2A regulates the pro-apoptotic activity of FOXO1. Biol Chem 283:7411–7420

    Article  CAS  Google Scholar 

  13. Villunger A, Scott C, Bouillet P, Strasser A (2003) Essential role for the BH3-only protein Bim, but redundant roles for Bax, Bcl-2, and Bcl-w in the control of granulocyte survival. Blood 101:2393–2400

    Article  CAS  PubMed  Google Scholar 

  14. Bauer A, Kirschnek S, Häcker G (2007) Inhibition of apoptosis can be accompanied by increased Bim levels in T lymphocytes and neutrophil granulocytes. Cell Death Differ 14:1714–1716

    Article  CAS  PubMed  Google Scholar 

  15. Chen D, Zhou Q (2004) Caspase cleavage of BimEL triggers a positive feedback amplification of apoptotic signaling. Proc Natl Acad Sci USA 101:1235–1240

    Article  CAS  PubMed  Google Scholar 

  16. Liu JW, Chandra D, Tang SH, Chopra D, Tang DG (2002) Identification and characterization of Bim γ, a novel proapoptotic BH3-only splice variant of Bim. Cancer Res 62:2976–2981

    CAS  PubMed  Google Scholar 

  17. Gilley J, Coffer PJ, Ham J (2003) FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 162:613–622

    Article  CAS  PubMed  Google Scholar 

  18. Stahl M, Dijkers PF, Kops GJ, Lens SM, Coffer PJ, Burgering BM, Medema RH (2002) The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol 168:5024–5031

    CAS  PubMed  Google Scholar 

  19. Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ (2000) Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol 10:1201–1204

    Article  CAS  PubMed  Google Scholar 

  20. Rahmani M, Yu C, Reese E, Ahmed W, Hirsch K, Dent P, Grant S (2003) Inhibition of PI-3 kinases ensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42MAP kinasein activation and abrogation of p21(CIP1/WAF1) induction rather than AKT inhibition. Oncogene 22:6231–6242

    Article  CAS  PubMed  Google Scholar 

  21. Yu C, Rahmani M, Conrad D, Subler M, Dent P, Grant S (2003) The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl + cells sensitive and resistant to STI571. Blood 102:3765–3774

    Article  CAS  PubMed  Google Scholar 

  22. Opel D, Westhoff MA, Bender A, Braun V, Debatin KM, Fulda S (2008) Phosphatidylinositol 3-kinase inhibition broadly sensitizes glioblastoma cells to death receptor- and drug-induced apoptosis. Cancer Res 68:6271–6280

    Article  CAS  PubMed  Google Scholar 

  23. Liu SQ, Yu JP, Yu HG, Lv P, Chen HL (2006) Activation of Akt and ERK signalling pathways induced by etoposide confer chemoresistance in gastric cancer cells. Dig Liver Dis 38:310–318

    Article  CAS  PubMed  Google Scholar 

  24. Liu P, Kao TP, Huang H (2008) CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor. Oncogene 27:4733–4744

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Liang Xiaohua.

Additional information

Zhan Qiong and Huang Ruofan have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qiong, Z., Ruofan, H., Xiaohua, L. et al. Role of dephosphorylation of FOXO1 on apoptosis induced by wortmannin for non-Hodgkin’s lymphoma cells. Mol Biol Rep 37, 2397–2402 (2010). https://doi.org/10.1007/s11033-009-9748-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-009-9748-3

Keywords

Navigation