Targeting peroxiredoxin I potentiates 1,25‑dihydroxyvitamin D3‑induced cell differentiation in leukemia cells

Wei,Wei; Liu,Chuanxu; Qin,Dongjun; Song,Lili; Xia,Li; Lei,Hu; Yu,Yun; Wang,Weiwei; Pu,Jianxin; Sun,Handong; Wu,Yingli; Xu,Hanzhang; Hao,Siguo

doi:10.3892/mmr.2016.4787

Targeting peroxiredoxin I potentiates 1,25‑dihydroxyvitamin D3‑induced cell differentiation in leukemia cells

Authors:
- Wei Wei
- Chuanxu Liu
- Dongjun Qin
- Lili Song
- Li Xia
- Hu Lei
- Yun Yu
- Weiwei Wang
- Jianxin Pu
- Handong Sun
- Yingli Wu
- Hanzhang Xu
- Siguo Hao
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Affiliations: Department of Hematology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China, Department of Pathophysiology, Chemical Biology Division of Shanghai Universities E‑Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China, State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650201, P.R. China
Published online on: January 14, 2016 https://doi.org/10.3892/mmr.2016.4787
Pages: 2201-2207

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Abstract

Although 1,25‑dihydroxyvitamin D3 (VD3) is regarded as a promising inducing agent for leukemia cell differentiation, it is not as effective an agent as all‑trans‑retinoic acid, and its usefulness is also limited by the adverse effects of hypercalcemia. The aim of the present study was to determine whether combining VD3 with adenanthin, a peroxiresoxin I (Prx I)‑targeting natural compound, improves the efficacy of VD3. Cell viability was assessed using a trypan blue exclusion assay and flow cytometry was used to evaluate the expression of cell surface markers, CD11b/CD14, and the level of reactive oxygen species (ROS). Wright's staining was used to examine morphological changes and RNA‑interference was used to knockdown Prx I and p65 gene expression. Protein expression was determined by western blot analysis. The results demonstrated that adenanthin markedly enhanced VD3‑induced cell differentiation of leukemia NB4 cells, as evidenced by the increased percentage of CD11b‑ and CD14‑positive cells, the mature morphology of the monocytes and the increased phagocytic ability. Consistent with these results, knockdown of Prx I, but not nuclear factor‑κB (p65), enhanced VD3‑induced cell differentiation. The combinatorial effects of adenanthin and VD3 were shown to be associated with the ROS‑CCAAT‑enhancer‑binding protein (C/EBP)β axis, since N‑acetylcysteine, a ROS scavenger, was able to abrogate the differentiation‑enhancing effects of adenanthin, and the knockdown of C/EBPβ also inhibited the combinatorial effects of adenanthin and VD3. In addition, co‑treatment with adenanthin and VD3 was able to induce differentiation in other non‑acute promyelocytic leukemia cells and primary leukemia cells. In conclusion, the results of the present study revealed a novel role for Prx I in VD3‑induced cell differentiation, and suggested that targeting Prx I may represent a novel strategy to enhance VD3‑induced leukemia cell differentiation.

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1	Gocek E and Marcinkowska E: Differentiation therapy of acute myeloid leukemia. Cancers (Basel). 3:2402–2420. 2011. View Article : Google Scholar
2	Hughes PJ, Marcinkowska E, Gocek E, Studzinski GP and Brown G: Vitamin D3-driven signals for myeloid cell differentiation – implications for differentiation therapy. Leuk Res. 34:553–565. 2010. View Article : Google Scholar :
3	Marchwicka A, Cebrat M, Sampath P, Snieżewski L and Marcinkowska E: Perspectives of differentiation therapies of acute myeloid leukemia: The search for the molecular basis of patients' variable responses to 1,25-dihydroxyvitamin D and vitamin D analogs. Front Oncol. 4:1252014. View Article : Google Scholar : PubMed/NCBI
4	Trump DL, Deeb KK and Johnson CS: Vitamin D: Considerations in the continued development as an agent for cancer prevention and therapy. Cancer J. 16:1–9. 2010. View Article : Google Scholar : PubMed/NCBI
5	Gocek E, Kiełbiński M, Baurska H, Haus O, Kutner A and Marcinkowska E: Different susceptibilities to 1,25-dihydroxyvitamin D3-induced differentiation of AML cells carrying various mutations. Leuk Res. 34:649–657. 2010. View Article : Google Scholar
6	Gocek E, Marchwicka A, Baurska H, Chrobak A and Marcinkowska E: Opposite regulation of vitamin D receptor by ATRA in AML cells susceptible and resistant to vitamin D-induced differentiation. J Steroid Biochem Mol Biol. 132:220–226. 2012. View Article : Google Scholar : PubMed/NCBI
7	Lee HJ, Muindi JR, Tan W, Hu Q, Wang D, Liu S, Wilding GE, Ford LA, Sait SN, Block AW, et al: Low 25(OH) vitamin D3 levels are associated with adverse outcome in newly diagnosed, intensively treated adult acute myeloid leukemia. Cancer. 120:521–529. 2014. View Article : Google Scholar :
8	Donovan PJ, Sundac L, Pretorius CJ, d'Emden MC and McLeod DS: Calcitriol-mediated hypercalcemia: Causes and course in 101 patients. J Clin Endocrinol Metab. 98:4023–4029. 2013. View Article : Google Scholar : PubMed/NCBI
9	Bae JY, Kim JW and Kim I: Low-dose 1,25-dihydroxyvitamin D(3) combined with arsenic trioxide synergistically inhibits proliferation of acute myeloid leukemia cells by promoting apoptosis. Oncol Rep. 30:485–491. 2013.PubMed/NCBI
10	Clark CS, Konyer JE and Meckling KA: 1alpha,25-dihydroxyvitamin D3 and bryostatin-1 synergize to induce monocytic differentiation of NB4 acute promyelocytic leukemia cells by modulating cell cycle progression. Exp Cell Res. 294:301–311. 2004. View Article : Google Scholar : PubMed/NCBI
11	Kim DS, Kim SH, Song JH, Chang YT, Hwang SY and Kim TS: Enhancing effects of ceramide derivatives on 1,25-dihydroxyvitamin D(3)-induced differentiation of human HL-60 leukemia cells. Life Sci. 81:1638–1644. 2007. View Article : Google Scholar : PubMed/NCBI
12	Kim SH, Yoo JC and Kim TS: Nargenicin enhances 1,25-dihydroxyvitamin D(3)- and all-trans retinoic acid-induced leukemia cell differentiation via PKCbetaI/MAPK pathways. Biochem Pharmacol. 77:1694–1701. 2009. View Article : Google Scholar : PubMed/NCBI
13	Wang Q, Harrison JS, Uskokovic M, Kutner A and Studzinski GP: Translational study of vitamin D differentiation therapy of myeloid leukemia: Effects of the combination with a p38 MAPK inhibitor and an antioxidant. Leukemia. 19:1812–1817. 2005. View Article : Google Scholar : PubMed/NCBI
14	Wang Q, Salman H, Danilenko M and Studzinski GP: Cooperation between antioxidants and 1,25-dihydroxyvitamin D3 in induction of leukemia HL60 cell differentiation through the JNK/AP-1/Egr-1 pathway. J Cell Physiol. 204:964–974. 2005. View Article : Google Scholar : PubMed/NCBI
15	Yang J, Ikezoe T, Nishioka C, Ni L, Koeffler HP and Yokoyama A: Inhibition of mTORC1 by RAD001 (everolimus) potentiates the effects of 1,25-dihydroxyvitamin D(3) to induce growth arrest and differentiation of AML cells in vitro and in vivo. Exp Hematol. 38:666–676. 2010. View Article : Google Scholar : PubMed/NCBI
16	Irwin ME, Rivera-Del Valle N and Chandra J: Redox control of leukemia: From molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 18:1349–1383. 2013. View Article : Google Scholar :
17	Hole PS, Darley RL and Tonks A: Do reactive oxygen species play a role in myeloid leukemias? Blood. 117:5816–5826. 2011. View Article : Google Scholar : PubMed/NCBI
18	Yamamoto T, Sakaguchi N, Hachiya M, Nakayama F, Yamakawa M and Akashi M: Role of catalase in monocytic differentiation of U937 cells by TPA: Hydrogen peroxide as a second messenger. Leukemia. 23:761–769. 2009. View Article : Google Scholar
19	Bondza-Kibangou P, Millot C, El Khoury V and Millot JM: Antioxidants and doxorubicin supplementation to modulate CD14 expression and oxidative stress induced by vitamin D3 and seocalcitol in HL60 cells. Oncol Rep. 18:1513–1519. 2007.PubMed/NCBI
20	Stixová L, Procházková J, Soucek K, Hofmanová J and Kozubík A: 5-Lipoxygenase inhibitors potentiate 1alpha,25-dihydroxyvitamin D3-induced monocytic differentiation by activating p38 MAPK pathway. Mol Cell Biochem. 330:229–238. 2009. View Article : Google Scholar : PubMed/NCBI
21	Callens C, Coulon S, Naudin J, Radford-Weiss I, Boissel N, Raffoux E, Wang PH, Agarwal S, Tamouza H, Paubelle E, et al: Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia. J Exp Med. 207:731–750. 2010. View Article : Google Scholar : PubMed/NCBI
22	Liu CX, Yin QQ, Zhou HC, Wu YL, Pu JX, Xia L, Liu W, Huang X, Jiang T, Wu MX, et al: Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells. Nat Chem Biol. 8:486–493. 2012. View Article : Google Scholar : PubMed/NCBI
23	Liu CX, Zhou HC, Yin QQ, Wu YL and Chen GQ: Targeting peroxiredoxins against leukemia. Exp Cell Res. 319:170–176. 2013. View Article : Google Scholar
24	Ishii T, Warabi E and Yanagawa T: Novel roles of peroxiredoxins in inflammation, cancer and innate immunity. J Clin Biochem Nutr. 50:91–105. 2012. View Article : Google Scholar : PubMed/NCBI
25	Ray PD, Huang BW and Tsuji Y: Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 24:981–990. 2012. View Article : Google Scholar : PubMed/NCBI
26	Owusu-Ansah E and Banerjee U: Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature. 461:537–541. 2009. View Article : Google Scholar : PubMed/NCBI
27	Ding Q, Jin T, Wang Z and Chen Y: Catalase potentiates retinoic acid-induced THP-1 monocyte differentiation into macrophage through inhibition of peroxisome proliferator-activated receptor gamma. J Leukoc Biol. 81:1568–1576. 2007. View Article : Google Scholar : PubMed/NCBI
28	Poole LB, Hall A and Nelson KJ: Overview of peroxiredoxins in oxidant defense and redox regulation. Curr Protoc Toxicol. Chapter 7: Unit7.9. 2011. View Article : Google Scholar : PubMed/NCBI
29	Zhang B, Wang Y and Su Y: Peroxiredoxins, a novel target in cancer radiotherapy. Cancer Lett. 286:154–160. 2009. View Article : Google Scholar : PubMed/NCBI
30	Tsukada J, Yoshida Y, Kominato Y and Auron PE: The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation. Cytokine. 54:6–19. 2011. View Article : Google Scholar : PubMed/NCBI
31	Huber R, Pietsch D, Panterodt T and Brand K: Regulation of C/EBPβ and resulting functions in cells of the monocytic lineage. Cell Signal. 24:1287–1296. 2012. View Article : Google Scholar : PubMed/NCBI
32	Ji Y and Studzinski GP: Retinoblastoma protein and CCAAT/enhancer-binding protein beta are required for 1,25-dihydroxyvitamin D3-induced monocytic differentiation of HL60 cells. Cancer Res. 64:370–377. 2004. View Article : Google Scholar : PubMed/NCBI
33	Marcinkowska E, Garay E, Gocek E, Chrobak A, Wang X and Studzinski GP: Regulation of C/EBPbeta isoforms by MAPK pathways in HL60 cells induced to differentiate by 1,25-dihydroxyvitamin D3. Exp Cell Res. 312:2054–2065. 2006. View Article : Google Scholar : PubMed/NCBI