Upregulation of AIOLOS induces apoptosis and enhances etoposide chemosensitivity in Jurkat leukemia cells

Zhuang,Yong; Lu,Yuanyuan; Li,Dong; Sun,Nianzheng; Ju,Xiuli

doi:10.3892/or.2014.3677

Upregulation of AIOLOS induces apoptosis and enhances etoposide chemosensitivity in Jurkat leukemia cells

Authors:
- Yong Zhuang
- Yuanyuan Lu
- Dong Li
- Nianzheng Sun
- Xiuli Ju
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Affiliations: Department of Pediatrics, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
Published online on: December 18, 2014 https://doi.org/10.3892/or.2014.3677
Pages: 1319-1325

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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder of immature hematopoietic precursors committed to T-cell lineage. T-ALL accounts for ~15% of pediatric ALL cases and is prone to early relapse. With new and improved treatment protocols, the prognosis of T-ALL has improved particularly in children; however, the outcome of relapsed T-ALL cases remains poor. The AIOLOS gene is necessary to control lymphocyte differentiation and may be a potential target of T-ALL therapy. In the present study, Jurkat cells were divided into three groups: untransfected (UT) control, lentiviral vector control (Lenti-Mock) and AIOLOS-overexpressing (Lenti-AIOLOS) groups. Lenti-AIOLOS Jurkat cells were constructed by lentiviral transduction; cell cycle analysis, apoptosis and cytotoxicity assays were then performed to evaluate the effects of AIOLOS on cell cycle distribution, apoptosis and cell chemosensitivity to etoposide of Jurkat cells in vitro. Moreover, the expression levels of genes associated with apoptosis and cell cycle were investigated by quantitative reverse transcription-polymerase chain reaction. Results showed that the percentage of Jurkat cells in the G0/G1 phase increased from 71.5 (UT) to 85.4% (Lenti-AIOLOS; P<0.05), yet the percentage of cells in the S-phase decreased from 15.1 (UT) to 11.6% (Lenti‑AIOLOS; P<0.05). The percentage of total apoptotic cells was significantly increased in the AIOLOS-transfected Jurkat cells (21.93%) compared with this percentage in the Lenti-Mock (13.35%) or the UT group (13.30%; P<0.05). Consistent with these results, AIOLOS overexpression induced P21 and P27 upregulation and CCND3 and SKP2 downregulation. Furthermore, AIOLOS overexpression synergistically increased the cytotoxic effects of etoposide and downregulated NF-κB expression. Our findings revealed that lentivirus-mediated AIOLOS overexpression in Jurkat cells induced cell apoptosis, arrested the cell cycle at the G0/G1 phase, and synergistically increased the sensitivity of Jurkat cells to etoposide by inhibiting NF-κB activity.

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1	Chiaretti S and Foà R: T-cell acute lymphoblastic leukemia. Haematologica. 94:160–162. 2009. View Article : Google Scholar : PubMed/NCBI
2	Pui CH, Robison LL and Look AT: Acute lymphoblastic leukaemia. Lancet. 371:1030–1043. 2008. View Article : Google Scholar : PubMed/NCBI
3	Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, Behm FG, Pui CH, Downing JR, Gilliland DG, Lander ES, Golub TR and Look AT: Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 1:75–87. 2002. View Article : Google Scholar : PubMed/NCBI
4	Pui CH and Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med. 354:166–178. 2006. View Article : Google Scholar : PubMed/NCBI
5	Bhojwani D and Pui CH: Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 14:e205–e217. 2013. View Article : Google Scholar : PubMed/NCBI
6	Kelley CM, Ikeda T, Koipally J, Avitahl N, Wu L, Georgopoulos K and Morgan BA: Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors. Curr Biol. 8:508–515. 1998. View Article : Google Scholar : PubMed/NCBI
7	Morgan B, Sun L, Avitahl N, Andrikopoulos K, Ikeda T, Gonzales E, Wu P, Neben S and Georgopoulos K: Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J. 16:2004–2013. 1997. View Article : Google Scholar : PubMed/NCBI
8	Georgopoulos K, Winandy S and Avitahl N: The role of the Ikaros gene in lymphocyte development and homeostasis. Ann Rev Immunol. 15:155–176. 1997. View Article : Google Scholar
9	Narvi E, Nera KP, Terho P, Mustonen L, Granberg J and Lassila O: Aiolos controls gene conversion and cell death in DT40 B cells. Scand J Immunol. 65:503–513. 2007. View Article : Google Scholar : PubMed/NCBI
10	Rebollo A, Ayllón V, Fleischer A, Martínez CA and Zaballos A: The association of Aiolos transcription factor and Bcl-x_L is involved in the control of apoptosis. J Immunol. 167:6366–6373. 2001. View Article : Google Scholar : PubMed/NCBI
11	Romero F, Martínez-A C, Camonis J and Rebollo A: Aiolos transcription factor controls cell death in T cells by regulating Bcl-2 expression and its cellular localization. EMBO J. 18:3419–3430. 1999. View Article : Google Scholar : PubMed/NCBI
12	Nakase K, Ishimaru F, Avitahl N, Dansako H, Matsuo K, Fujii K, Sezaki N, Nakayama H, Yano T, Fukuda S, Imajoh K, Takeuchi M, Miyata A, Hara M, Yasukawa M, Takahashi I, Taguchi H, Matsue K, Nakao S, Niho Y, Takenaka K, Shinagawa K, Ikeda K, Niiya K and Harada M: Dominant negative isoform of the Ikaros gene in patients with adult B-cell acute lymphoblastic leukemia. Cancer Res. 60:4062–4065. 2000.PubMed/NCBI
13	Nückel H, Frey UH, Sellmann L, Collins CH, Duhrsen U and Siffert W: The IKZF3 (Aiolos) transcription factor is highly upregulated and inversely correlated with clinical progression in chronic lymphocytic leukaemia. Br J Haematol. 144:268–270. 2009. View Article : Google Scholar
14	Billot K, Soeur J, Chereau F, Arrouss I, Merle-Beral H, Huang ME, Mazier D, Baud V and Rebollo A: Deregulation of Aiolos expression in chronic lymphocytic leukemia is associated with epigenetic modifications. Blood. 117:1917–1927. 2011. View Article : Google Scholar
15	Antica M, Cicin-Sain L, Kapitanovic S, Matulic M, Dzebro S and Dominis M: Aberrant Ikaros, Aiolos, and Helios expression in Hodgkin and non-Hodgkin lymphoma. Blood. 111:3296–3297. 2008. View Article : Google Scholar : PubMed/NCBI
16	Zhuang Y, Li D, Fu J, Shi Q, Lu Y and Ju X: Overexpression of AIOLOS inhibits cell proliferation and suppresses apoptosis in Nalm-6 cells. Oncol Rep. 31:1183–1190. 2014.PubMed/NCBI
17	Frescas D and Pagano M: Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer. Nat Rev Cancer. 8:438–449. 2008. View Article : Google Scholar : PubMed/NCBI
18	Hershko DD: Oncogenic properties and prognostic implications of the ubiquitin ligase Skp2 in cancer. Cancer. 112:1415–1424. 2008. View Article : Google Scholar : PubMed/NCBI
19	Wang Z, Fukushima H, Inuzuka H, Wan L, Liu P, Gao D, Sarkar FH and Wei W: Skp2 is a promising therapeutic target in breast cancer. Front Oncol. 1:pii: 18702. 2012. View Article : Google Scholar : PubMed/NCBI
20	Kitagawa M, Lee SH and McCormick F: Skp2 suppresses p53-dependent apoptosis by inhibiting p300. Mol Cell. 29:217–231. 2008. View Article : Google Scholar : PubMed/NCBI
21	Lin HK, Wang G, Chen Z, Teruya-Feldstein J, Liu Y, Chan CH, Yang WL, Erdjument-Bromage H, Nakayama KI, Nimer S, Tempst P and Pandolfi PP: Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB. Nat Cell Biol. 11:420–432. 2009. View Article : Google Scholar : PubMed/NCBI
22	Stella S, Tirrò E, Conte E, Stagno F, Di Raimondo F, Manzella L and Vigneri P: Suppression of survivin induced by a BCR-ABL/JAK2/STAT3 pathway sensitizes imatinib-resistant CML cells to different cytotoxic drugs. Mol Cancer Ther. 12:1085–1098. 2013. View Article : Google Scholar : PubMed/NCBI
23	Xiong H, Zhang ZG, Tian XQ, Sun DF, Liang QC, Zhang YJ, Lu R, Chen YX and Fang JY: Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia. 10:287–297. 2008.PubMed/NCBI
24	Kirkin V, Joos S and Zörnig M: The role of Bcl-2 family members in tumorigenesis. Biochim Biophys Acta. 1644:229–249. 2004. View Article : Google Scholar : PubMed/NCBI
25	Martins LM, Mesner PW, Kottke TJ, Basi GS, Sinha S, Tung JS, Svingen PA, Madden BJ, Takahashi A, McCormick DJ, Earnshaw WC and Kaufmann SH: Comparison of caspase activation and subcellular localization in HL-60 and K562 cells undergoing etoposide-induced apoptosis. Blood. 90:4283–4296. 1997.PubMed/NCBI
26	Montecucco A and Biamonti G: Cellular response to etoposide treatment. Cancer Lett. 252:9–18. 2007. View Article : Google Scholar
27	Karin M and Greten FR: NF-κB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 5:749–759. 2005. View Article : Google Scholar : PubMed/NCBI