Enhancement of differentiation induction and upregulation of CCAAT/enhancer-binding proteins and PU.1 in NB4 cells treated with combination of ATRA and valproic acid

Iriyama,Noriyoshi; Yuan,Bo; Yoshino,Yuta; Hatta,Yoshihiro; Horikoshi,Akira; Aizawa,Shin; Takei,Masami; Takeuchi,Jin; Takagi,Norio; Toyoda,Hiroo

doi:10.3892/ijo.2013.2236

Enhancement of differentiation induction and upregulation of CCAAT/enhancer-binding proteins and PU.1 in NB4 cells treated with combination of ATRA and valproic acid

Authors:
- Noriyoshi Iriyama
- Bo Yuan
- Yuta Yoshino
- Yoshihiro Hatta
- Akira Horikoshi
- Shin Aizawa
- Masami Takei
- Jin Takeuchi
- Norio Takagi
- Hiroo Toyoda
View Affiliations

Affiliations: Department of Hematology and Rheumatology, Nihon University School of Medicine, Itabashi Hospital, Itabashi-ku, Tokyo 173-8610, Japan, Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan, Department of Functional Morphology, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan, Department of Applied Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan
Published online on: December 30, 2013 https://doi.org/10.3892/ijo.2013.2236
Pages: 865-873

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The effects of all-trans retinoic acid (ATRA) and valproic acid (VPA), alone and in combination, on the human acute promyelocytic leukemia (APL) cell line NB4 were investigated in view of differentiation induction and growth inhibition. After 48 h of treatment, not only ATRA but also VPA induced differentiation in NB4 cells, and their combination further augmented the differentiation activity. Furthermore, the upregulation of transcription factors including CCAAT/enhancer-binding proteins (CEBPα, β, ε) and PU.1, which are known to be critical factors for normal myelopoiesis, granulocytic maturation and being repressed in APL, concurred with the differentiation induction. A significant cell growth inhibition was observed after the treatment with VPA, which was further strengthened by the addition of ATRA. Given the importance of C/EBPs and PU.1 in myeloid development, these results, thus, suggest that restoration of the normal function of the myeloid cell transcriptional machinery is a major molecular mechanism underlying the differentiation induction in NB4. Therefore, these results may provide novel insights into a possible combinational therapeutic approach for APL patients.

View Figures

View References

1.	Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S and Pelicci PG: Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature. 391:815–818. 1998. View Article : Google Scholar : PubMed/NCBI
2.	Lin RJ, Nagy L, Inoue S, Shao W, Miller WH Jr and Evans RM: Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature. 391:811–814. 1998. View Article : Google Scholar : PubMed/NCBI
3.	Fang J, Chen SJ, Tong JH, Wang ZG, Chen GQ and Chen Z: Treatment of acute promyelocytic leukemia with ATRA and As2O3: a model of molecular target-based cancer therapy. Cancer Biol Ther. 1:614–620. 2002. View Article : Google Scholar : PubMed/NCBI
4.	Wang ZY and Chen Z: Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 111:2505–2515. 2008. View Article : Google Scholar : PubMed/NCBI
5.	Zhang JW, Wang JY, Chen SJ and Chen Z: Mechanisms of all-trans retinoic acid-induced differentiation of acute promyelocytic leukemia cells. J Biosci. 25:275–284. 2000. View Article : Google Scholar : PubMed/NCBI
6.	Melnick A and Licht JD: Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood. 93:3167–3215. 1999.PubMed/NCBI
7.	Tallman MS and Altman JK: Curative strategies in acute promyelocytic leukemia. Hematology Am Soc Hematol Educ Program. 1:391–399. 2008. View Article : Google Scholar
8.	Thirugnanam R, George B, Chendamarai E, Lakshmi KM, Balasubramanian P, Viswabandya A, Srivastava A, Chandy M and Mathews V: Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant. 15:1479–1484. 2009. View Article : Google Scholar
9.	Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG and Heinzel T: Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20:6969–6978. 2001.PubMed/NCBI
10.	Quintás-Cardama A, Santos FP and Garcia-Manero G: Histone deacetylase inhibitors for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Leukemia. 25:226–235. 2011.PubMed/NCBI
11.	Bolden JE, Peart MJ and Johnstone RW: Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov. 5:769–784. 2006. View Article : Google Scholar : PubMed/NCBI
12.	Cheng YC, Lin H, Huang MJ, Chow JM, Lin S and Liu HE: Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia. Leuk Res. 31:1403–1411. 2007. View Article : Google Scholar : PubMed/NCBI
13.	Cimino G, Lo-Coco F, Fenu S, Travaglini L, Finolezzi E, Mancini M, Nanni M, Careddu A, Fazi F, Padula F, Fiorini R, Spiriti MA, Petti MC, Venditti A, Amadori S, Mandelli F, Pelicci PG and Nervi C: Sequential valproic acid/all-trans retinoic acid treatment reprograms differentiation in refractory and high-risk acute myeloid leukemia. Cancer Res. 66:8903–8911. 2006. View Article : Google Scholar : PubMed/NCBI
14.	Kuendgen A, Schmid M, Schlenk R, Knipp S, Hildebrandt B, Steidl C, Germing U, Haas R, Dohner H and Gattermann N: The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer. 106:112–119. 2006. View Article : Google Scholar : PubMed/NCBI
15.	Kuendgen A, Strupp C, Aivado M, Bernhardt A, Hildebrandt B, Haas R, Germing U and Gattermann N: Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood. 104:1266–1269. 2004. View Article : Google Scholar : PubMed/NCBI
16.	Duprez E, Wagner K, Koch H and Tenen DG: C/EBPbeta: a major PML-RARA-responsive gene in retinoic acid-induced differentiation of APL cells. EMBO J. 22:5806–5816. 2003. View Article : Google Scholar : PubMed/NCBI
17.	Guibal FC, Alberich-Jorda M, Hirai H, Ebralidze A, Levantini E, Di Ruscio A, Zhang P, Santana-Lemos BA, Neuberg D, Wagers AJ, Rego EM and Tenen DG: Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia. Blood. 114:5415–5425. 2009. View Article : Google Scholar : PubMed/NCBI
18.	Mueller BU, Pabst T, Fos J, Petkovic V, Fey MF, Asou N, Buergi U and Tenen DG: ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood. 107:3330–3338. 2006. View Article : Google Scholar : PubMed/NCBI
19.	Park DJ, Chumakov AM, Vuong PT, Chih DY, Gombart AF, Miller WH Jr and Koeffler HP: CCAAT/enhancer binding protein epsilon is a potential retinoid target gene in acute promyelocytic leukemia treatment. J Clin Invest. 103:1399–1408. 1999. View Article : Google Scholar : PubMed/NCBI
20.	Rosmarin AG, Yang Z and Resendes KK: Transcriptional regulation in myelopoiesis: Hematopoietic fate choice, myeloid differentiation, and leukemogenesis. Exp Hematol. 33:131–143. 2005. View Article : Google Scholar : PubMed/NCBI
21.	Zhang K, Li J, Meng W, Xing H and Yang Y: C/EBPbeta and CHOP participate in tanshinone IIA-induced differentiation and apoptosis of acute promyelocytic leukemia cells in vitro. Int J Hematol. 92:571–578. 2010. View Article : Google Scholar : PubMed/NCBI
22.	Tenen DG: Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer. 3:89–101. 2003. View Article : Google Scholar : PubMed/NCBI
23.	Yoshino Y, Yuan B, Kaise T, Takeichi M, Tanaka S, Hirano T, Kroetz DL and Toyoda H: Contribution of aquaporin 9 and multidrug resistance-associated protein 2 to differential sensitivity to arsenite between primary cultured chorion and amnion cells prepared from human fetal membranes. Toxicol Appl Pharmacol. 257:198–208. 2011. View Article : Google Scholar
24.	Iriyama N, Yuan B, Hatta Y, Horikoshi A, Yoshino Y, Toyoda H, Aizawa S and Takeuchi J: Granulocyte colony-stimulating factor potentiates differentiation induction by all-trans retinoic acid and arsenic trioxide and enhances arsenic uptake in the acute promyelocytic leukemia cell line HT93A. Oncol Rep. 28:1875–1882. 2012.
25.	Yuan B, Ohyama K, Takeichi M and Toyoda H: Direct contribution of inducible nitric oxide synthase expression to apoptosis induction in primary smooth chorion trophoblast cells of human fetal membrane tissues. Int J Biochem Cell Biol. 41:1062–1069. 2009. View Article : Google Scholar
26.	Kosugi H, Towatari M, Hatano S, Kitamura K, Kiyoi H, Kinoshita T, Tanimoto M, Murate T, Kawashima K, Saito H and Naoe T: Histone deacetylase inhibitors are the potent inducer/enhancer of differentiation in acute myeloid leukemia: a new approach to anti-leukemia therapy. Leukemia. 13:1316–1324. 1999. View Article : Google Scholar : PubMed/NCBI
27.	Morosetti R, Park DJ, Chumakov AM, Grillier I, Shiohara M, Gombart AF, Nakamaki T, Weinberg K and Koeffler HP: A novel, myeloid transcription factor, C/EBP epsilon, is upregulated during granulocytic, but not monocytic, differentiation. Blood. 90:2591–2600. 1997.PubMed/NCBI
28.	Inazawa Y, Saeki K and Yuo A: Granulocyte colony-stimulating factor-induced terminal maturation of human myeloid cells is specifically associated with up-regulation of receptor-mediated function and CD10 expression. Int J Hematol. 77:142–151. 2003. View Article : Google Scholar
29.	Zhao Q, Tao J, Zhu Q, Jia PM, Dou AX, Li X, Cheng F, Waxman S, Chen GQ, Chen SJ, Lanotte M, Chen Z and Tong JH: Rapid induction of cAMP/PKA pathway during retinoic acid-induced acute promyelocytic leukemia cell differentiation. Leukemia. 18:285–292. 2004. View Article : Google Scholar : PubMed/NCBI
30.	Zhang K, Guo QL, You QD, Yang Y, Zhang HW, Yang L, Gu HY, Qi Q, Tan Z and Wang X: Wogonin induces the granulocytic differentiation of human NB4 promyelocytic leukemia cells and up-regulates phospholipid scramblase 1 gene expression. Cancer Sci. 99:689–695. 2008. View Article : Google Scholar : PubMed/NCBI
31.	Kawagoe R, Kawagoe H and Sano K: Valproic acid induces apoptosis in human leukemia cells by stimulating both caspase-dependent and -independent apoptotic signaling pathways. Leuk Res. 26:495–502. 2002. View Article : Google Scholar : PubMed/NCBI
32.	Leiva M, Moretti S, Soilihi H, Pallavicini I, Peres L, Mercurio C, Dal Zuffo R, Minucci S and de Thé H: Valproic acid induces differentiation and transient tumor regression, but spares leukemia-initiating activity in mouse models of APL. Leukemia. 26:1630–1637. 2012. View Article : Google Scholar : PubMed/NCBI
33.	Deubzer H, Busche B, Rönndahl G, Eikel D, Michaelis M, Cinatl J, Schulze S, Nau H and Witt O: Novel valproic acid derivatives with potent differentiation-inducing activity in myeloid leukemia cells. Leuk Res. 30:1167–1175. 2006. View Article : Google Scholar : PubMed/NCBI
34.	Zapotocky M, Mejstrikova E, Smetana K, Stary J, Trka J and Starkova J: Valproic acid triggers differentiation and apoptosis in AML1/ETO-positive leukemic cells specifically. Cancer Lett. 319:144–153. 2012. View Article : Google Scholar : PubMed/NCBI
35.	Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, Rosenblatt J, Avigan DE, Teruya-Feldstein J and Pandolfi PP: PML targeting eradicates quiescent leukaemia-initiating cells. Nature. 453:1072–1078. 2008. View Article : Google Scholar : PubMed/NCBI
36.	Yuan B, Yoshino Y, Kaise T and Toyoda H: Application of arsenic trioxide therapy for patients with leukemia. Biological Chemistry of Arsenic, Antimony and Bismuth. Sun H: John Wiley & Sons, Ltd; Chichester: pp. 263–292. 2011