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Bortezomib induces apoptosis by interacting with JAK/STAT pathway in K562 leukemic cells

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Tumor Biology

Abstract

In the current study, we aimed to identify the cytotoxic and apoptotic effects of bortezomib (BOR) on human K562 chronic myelogenous leukemia cells and to evaluate the potential roles of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway members STAT3, STAT5, and JAK2 on BOR-induced cell death of leukemic cells. Cell viability was assessed via trypan blue dye exclusion test, and cytotoxicity of the BOR-treated cells was conducted by 2,3-bis(2-methoxy-4-nitro-5-sulphophenyl)-2H-tetrazolium-5-carboxanilide inner salt (XTT) assay. The relative messenger RNA (mRNA) expression levels of STAT3, STAT5A, STAT5B, and JAK2 were analyzed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). On the other hand, their protein expression levels were detected by western blot method. The obtained results indicated that BOR treatment reduced cell viability and induced leukemic cell apoptosis in a dose- and time-dependent manner as compared to untreated control cells. While mRNA expression levels of STAT5A, STAT5B, and STAT3 were significantly reduced following BOR treatment when compared to untreated controls, it had no effect upon JAK2 mRNA expression. As for protein levels, STAT expressions were downregulated after BOR treatment especially at 72nd and 96th hours. Our results pointed out that BOR treatment had a significant potential of being an anticancer agent for chronic myelogenous leukemia therapy, and this effect could be due to the expressional downregulations of JAK/STAT pathway members.

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References

  1. Nasr R, Bazarbachi A. Chronic myeloid leukemia. "Archetype" of the impact of targeted therapies. Pathol Biol. 2012;60(4):230–45.

    Article  Google Scholar 

  2. Ramirez P, Dipersio JP. Therapy options in imatinib failures. The Oncologist Leukemias. 2008;13:424–34.

    Article  CAS  Google Scholar 

  3. Bixby DL. Managing inadequate responses to frontline treatment of chronic myeloid leukemia: a case-based review. Cancer Treat Rev. 2013;39(3):241–51.

    Article  PubMed  Google Scholar 

  4. Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119(5):1123–9.

    Article  CAS  PubMed  Google Scholar 

  5. Steinberg M, Steinberg M. BCOP. New drug dasatinib: a tyrosine kinase inihibitor for the treatment of chronic myelegenous leukemia and philadelphia chrosome-positive acute lymphoblastic leukemia. Clinical Thepeutics. 2007;29(11):2289–308.

    Article  CAS  Google Scholar 

  6. Smoak KA, Cidlowski JA. Mechanisms of glucocorticoid receptor signaling during inflammation. Mech Ageing Dev. 2004;125:697–706.

    Article  CAS  PubMed  Google Scholar 

  7. Bromberg JF. Activation of STAT proteins and growth control. Biogeosciences. 2001;23:161–9.

    CAS  Google Scholar 

  8. Bromberg J. Stat proteins and oncogenesis. J Clin Invest. 2002;109:1139–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Catlett-Falcone R, Landowski TH, Oshiro MM, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity. 1999;10:105–15.

    Article  CAS  PubMed  Google Scholar 

  10. Levy DE, Gilliland DG. Divergent roles of Stat1 and Stat5 in malignancy as revealed by gene disruptions in mice. Oncogene. 2000;19:2505–10.

    Article  CAS  PubMed  Google Scholar 

  11. Costa-Pereira AP, Bonito NA, Seckl MJ. Dysregulation of janus kinases and signal transducers and activators of transcription in cancer. Am J Cancer Res. 2011;1(6):806–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Richardson PG, Hideshima T, Anderson KC. Bortezomib (PS-341). A novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancer. Cancer Control. 2003;10(5):361–9.

    PubMed  Google Scholar 

  13. Kaymaz BT, Selvi N, Saydam G, Şahin F, Kosova B. Methylprednisolone induces apoptosis by interacting with the JAK/STAT pathway in HL–60 and K–562 leukemic cells. Hematology. 2012;17(2):93–9.

    Article  CAS  PubMed  Google Scholar 

  14. Lee Jr JT, McCubrey JA. The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention in leukemia. Leukemia. 2002;16:486–507.

    Article  CAS  PubMed  Google Scholar 

  15. Steelman LS, Abrams SL, Whelan J, Bertrand FE, Ludwig DE, Bäsecke J, et al. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia. 2008;22(4):686–707.

    Article  CAS  PubMed  Google Scholar 

  16. McCubrey JA, Steelman LS, Abrams SL, Bertrand FE, Ludwig DE, Bäsecke J, et al. Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia. 2008;22(4):708–22. Review.

    Article  CAS  PubMed  Google Scholar 

  17. Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 2004;18(2):189–218. Review.

    Article  CAS  PubMed  Google Scholar 

  18. Sacha T, Hochaus A, Hanfstein B, Muller MC, Rudzki Z, Czopek J, et al. Abl-kinase domain point mutation as a cause of imatinib crisis. Leuk Res. 2003;27:1163–6.

    Article  CAS  PubMed  Google Scholar 

  19. Hochaus A. Cytogenetic and molecular mechanisms of resistance to imatinib. Semin Hematol. 2003;40:69–79.

    Article  Google Scholar 

  20. Tipping AJ, Melo JV. Imatinib mesylate in combination with other chemotherapeutic drugs: in vitro studies. Semin Hematol. 2003;40:83–91.

    Article  CAS  PubMed  Google Scholar 

  21. Roche-Lestiennc C, Preudhomme C. Mutations in the Abl kinase domain pre-exist the conset of imatinib treatment. Semin Hematol. 2003;40:80–2.

    Article  Google Scholar 

  22. Zheng B, Zhou R, Gong Y, Yang X, Shan Q. Proteasome inhibitor bortezomib overcomes P-gp-mediated multidrug resistance in resistant leukemic cell lines. Int Jnl Lab Hem. 2012;34:237–47.

    Article  CAS  Google Scholar 

  23. Zhou Y, Ma LM, Li XY, Zhang HP, Wang T, Niu YY, et al. Effect of bortezomib on the drug sensitivity of imatinib resistant K562/G01 cells. Zhonghua Xue Ye Xue Za Zhi. 2011;32(6):292–5.

    Google Scholar 

  24. Danial NN, Pernis A, Rothman PB. Jak–STAT signaling induced by the v-abl oncogene. Science. 1995;269:1875–7.

    Article  CAS  PubMed  Google Scholar 

  25. Danial NN, Rothman P. JAK–STAT signaling activated by Abl oncogenes. Oncogene. 2000;19:2523–31.

    Article  CAS  PubMed  Google Scholar 

  26. Migone TS, Lin JX, Cereseto A, Mulloy JC, O’Shea JJ, Franchini G, et al. Constitutively activated Jak–STAT pathway in T cells transformed with HTLV-I. Science. 1995;269:79–81.

    Article  CAS  PubMed  Google Scholar 

  27. Muj Taba T, Dou QP. Advences in the understanding of mechanism and therapeutic use of Bortezomib. Discov Med. 2011;12(67):471–80.

    Google Scholar 

  28. Qui X, Guo G, Chen K, Kashiwada M, Druker BJ, Rothman PB, et al. A requirement for SOCS-1 and SOCS-3 phosphorylation in Bcr–ABL–induced tumorigenesis. Neoplasia. 2012;14(6):547–58.

    Google Scholar 

  29. Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 2004;18:189–218.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Biology, Medical Faculty, Ege University, Bornova, 35100, Izmir, Turkey

    Nur Selvi, Burçin Tezcanli Kaymaz, Cumhur Gündüz, Çağdaş Aktan & Buket Kosova

  2. Department of Haemotology, Medical Faculty, Ege University, Bornova, 35100, Izmir, Turkey

    Hatice Demet Kiper, Fahri Şahin, Melda Cömert & Güray Saydam

  3. Selimiye State Hospital, 22030, Edirne, Turkey

    Ali Fatih Selvi

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  1. Nur Selvi
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  2. Burçin Tezcanli Kaymaz
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  8. Ali Fatih Selvi
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Correspondence to Nur Selvi.

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Selvi, N., Kaymaz, B.T., Gündüz, C. et al. Bortezomib induces apoptosis by interacting with JAK/STAT pathway in K562 leukemic cells. Tumor Biol. 35, 7861–7870 (2014). https://doi.org/10.1007/s13277-014-2048-0

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  • DOI: https://doi.org/10.1007/s13277-014-2048-0

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