Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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Advances in Clinical and Experimental Medicine

2017, vol. 26, nr 9, December, p. 1335–1342

doi: 10.17219/acem/65475

Publication type: original article

Language: English

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Transcriptomic analysis of the PI3K/Akt signaling pathway reveals the dual role of the c-Jun oncogene in cytotoxicity and the development of resistance in HL-60 leukemia cells in response to arsenic trioxide

Joanna Roszak1,A,B,C,D, Anna Smok-Pieniążek1,B, Maciej Stępnik1,A,C,D,E,F

1 Nofer Institute of Occupational Medicine, Łódź, Poland

Abstract

Background. Arsenic trioxide (ATO) is a well-recognized antileukemic drug used for the treatment of newly diagnosed and relapsed acute promyelocytic leukemia (APL). A major drawback of therapy with ATO is the development of APL cell resistance, the mechanisms of which are still not clear.
Objectives. The aim of this study was to investigate the role of the PI3K/Akt signaling pathway in ATOtreated human acute myeloid leukemia (HL-60) cells and in ATO-resistant clones.
Material and Methods. The cytotoxicity of ATO was assessed using Trypan blue staining or a WST-1 reduction assay. The Akt phosphorylation level was measured by immunofluorescent staining and flow cytometry. Gene expression analysis was performed using real-time polymerase chain reaction (PCR).
Results. The clones derived by culturing for 8–12 weeks in the presence of 1.75, 2.5, and 5 μM ATO were characterized by high viability but a slower growth rate compared to the parental HL-60 cells. The flow cytometry analysis showed that in the parental cells the levels of p-Akt were undetectable or very low, and that ATO had no effect on the level of p-Akt in either the ATO-treated parental cells or the clones. The gene expression analysis revealed that some of the genes involved in the Akt pathway may play a key role in the induction of resistance to ATO, e.g., genes encoding cyclin D1 (CCND1), fork head box O1 (FOXO1), Jun oncogene (JUN), protein kinase C isoform B1 (PRKCB1), because their expression profiles were predominantly changed in the clones and/or the ATO-treated parental HL-60 cells.
Conclusion. The overall results indicate that CCND1, FOXO1, and JUN may contribute to the induction of resistance to ATO, and that the C-Jun N-terminal kinase (JNK) signaling pathway may have greater significance than the phosphoinositide 3-kinase (PI3K)/Akt pathway in mediating the cytotoxic effects of ATO and the development of resistance to ATO in the HL-60 cell line.

Key words

Akt kinase, C-Jun, arsenic trioxide, HL-60 cells, arsenic resistant clones

References (29)

  1. Norsworthy KJ, Altman JK. Optimal treatment strategies for high-risk acute promyelocytic leukemia. Curr Opin Hematol. 2016;23:127–136.
  2. Mi JQ, Chen SJ, Zhou GB, Yan XJ, Chen Z. Synergistic targeted therapy for acute promyelocytic leukaemia: A model of translational research in human cancer. J Intern Med. 2015;278:627–642.
  3. Wang S, Zhou M, Ouyang J, Geng Z, Wang Z. Tetraarsenic tetrasulfide and arsenic trioxide exert synergistic effects on induction of apoptosis and differentiation in acute promyelocytic leukemia cells. PLoS One. 2015;10:e0130343.
  4. Zhu HH, Qin YZ, Huang XJ. Resistance to arsenic therapy in acute promyelocytic leukemia. N Engl J Med. 2014;370:1864–1866.
  5. Lehmann-Che J, Bally C, de Thé H. Resistance to therapy in acute promyelocytic leukemia. N Engl J Med. 2014;371:1170–1172.
  6. Tabellini G, Tazzari PL, Bortul R, et al. Phosphoinositide 3-kinase/Akt inhibition increases arsenic trioxide-induced apoptosis of acute promyelocytic and T-cell leukaemias. Br J Haematol. 2005;130:716–725.
  7. Roy NK, Bordoloi D, Monisha J, et al. Specific targeting of Akt kinase isoforms: Taking the precise path for prevention and treatment of cancer. Curr Drug Targets. 2016;7. [Epub ahead of print]
  8. Bornhauser BC, Bonapace L, Lindholm D, et al. Low-dose arsenic trioxide sensitizes glucocorticoid-resistant acute lymphoblastic leukemia cells to dexamethasone via an Akt-dependent pathway. Blood. 2007;110:2084–2091.
  9. Redondo-Muñoz J, Escobar-Díaz E, Hernández del Cerro M, et al. Induction of B-chronic lymphocytic leukemia cell apoptosis by arsenic trioxide involves suppression of the phosphoinositide 3-kinase/Akt survival pathway via c-jun-NH2 terminal kinase activation and PTEN upregulation. Clin Cancer Res. 2010;16:4382–4391.
  10. Mann KK, Colombo M, Miller WH Jr. Arsenic trioxide decreases AKT protein in a caspase-dependent manner. Mol Cancer Ther. 2008;7:1680–1687.
  11. Chen P, Wu JY, Huang HF, Chen YZ. The effect to IL-3R alpha, downstream PI3k/Akt signaling of all-trans retinoic acid and arsenic trioxide in NB4 cells. Pharmazie. 2014;69:297–300.
  12. Roszak J, Smok-Pieniążek A, Nocuń M, Stępnik M. Characterization of arsenic trioxide resistant clones derived from Jurkat leukemia T cell line: Focus on PI3K/Akt signaling pathway. Chem Biol Interact. 2013;205:198–211.
  13. Uddin S, Hussain A, Al-Hussein K, Platanias LC, Bhatia KG. Inhibition of phosphatidylinositol 3’-kinase induces preferentially killing of PTEN-null T leukemias through AKT pathway. Biochem Biophys Res Commun. 2004;320:932–938.
  14. Cully M, You H, Levine AJ, Mak TW. Beyond PTEN mutations: The PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. 2006;6:184–192.
  15. Uddin S, Hussain AR, Siraj AK, et al. Role of phosphatidylinositol 3’-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood. 2006;108:4178–4186.
  16. Evens AM, Tallman MS, Gartenhaus RB. The potential of arsenic trioxide in the treatment of malignant disease: Past, present, and future. Leuk Res. 2004;28:891–900.
  17. Douer D, Tallman MS. Arsenic trioxide: New clinical experience with an old medication in hematologic malignancies. J Clin Oncol. 2005;23:2396–2410.
  18. Choi YJ, Park JW, Suh SI, et al. Arsenic trioxide-induced apoptosis in U937 cells involve generation of reactive oxygen species and inhibition of Akt. Int J Oncol. 2002;21:603–610.
  19. Deng B, Xie S, Wang J, Xia Z, Nie R. Inhibition of protein kinase C β(2) prevents tumor necrosis factor-α-induced apoptosis and oxidative stress in endothelial cells: The role of NADPH oxidase subunits. J Vasc Res. 2012;49:144–159.
  20. Herbst RS, Oh Y, Wagle A, Lahn M. Enzastaurin, a protein kinase Cβ-selective inhibitor, and its potential application as an anticancer agent in lung cancer. Clinical Cancer Research. 2007;13;4641s–4646s.
  21. Wu Y, Dai J, ZhangW, et al. Arsenic trioxide induces apoptosis in human platelets via C-Jun NH2-terminal kinase activation. PLoS One. 2014;9:e86445.
  22. Schütte J, Viallet J, Nau M, et al. jun-B inhibits and c-fos stimulates the transforming and trans-activating activities of c-jun. Cell. 1989;59:987–997.
  23. Heidari N, Miller AV, Hicks MA, Marking CB, Harada H. Glucocorticoid-mediated BIM induction and apoptosis are regulated by Runx2 and c-Jun in leukemia cells. Cell Death Dis. 2012;3:e349.
  24. Kuida K, Lippke JA, Ku G, et al. Altered cytokine export and apoptosis in mice deficient in interleukin-1 beta converting enzyme. Science. 1995;267:2000–2003.
  25. Mechta-Grigoriou F, Gerald D, Yaniv M. The mammalian Jun proteins: Redundancy and specificity. Oncogene. 2001;20:2378–2389.
  26. Cappellini A, Tabellini G, Zweyer M, et al. The phosphoinositide 3-kinase/Akt pathway regulates cell cycle progression of HL60 human leukemia cells through cytoplasmic relocalization of the cyclin-dependent kinase inhibitor p27(Kip1) and control of cyclin D1 expression. Leukemia. 2003;17:2157–2167.
  27. Alikhani M, Roy S, Graves DT. FOXO1 plays an essential role in apoptosis of retinal pericytes. Mol Vis. 2010;16:408–415.
  28. van den Berg MC, Burgering BM. Integrating opposing signals toward Forkhead box O. Antioxid Redox Signal. 2011;14:607–621.
  29. Grabiec AM, Angiolilli C, Hartkamp LM, et al. JNK-dependent downregulation of FOXO1 is required to promote the survival of fibroblast-like synoviocytes in rheumatoid arthritis. Ann Rheum Dis. 2015;74:1763–1771.
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