SIRT2 mediates multidrug resistance in acute myelogenous leukemia cells via ERK1/2 signaling pathway

Xu,Hua; Li,Yuanye; Chen,Long; Wang,Chijuan; Wang,Qi; Zhang,Hairui; Lin,Yani; Li,Qinghua; Pang,Tianxiang

doi:10.3892/ijo.2015.3275

SIRT2 mediates multidrug resistance in acute myelogenous leukemia cells via ERK1/2 signaling pathway

Authors:
- Hua Xu
- Yuanye Li
- Long Chen
- Chijuan Wang
- Qi Wang
- Hairui Zhang
- Yani Lin
- Qinghua Li
- Tianxiang Pang
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Affiliations: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P.R. China
Published online on: December 7, 2015 https://doi.org/10.3892/ijo.2015.3275
Pages: 613-623

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Abstract

SIRT2, one of nicotinamide adenine dinucleotide (NAD+)-dependent class Ⅲ histone deacetylase family proteins, has been found to be involved in the proliferation and survival of acute myeloid leukemia (AML) cells. However, its effect on drug resistance on chemoresistant AML cells is unclear. In the present study, we first found that SIRT2 was expressed at higher level in the relapsed AML patients than the newly diagnosed patients. Consistent with this observation, the expression level of SIRT2 was higher in HL60/A cells than that in HL60 cells. Depletion of SIRT2 by shRNAs in HL60/A cells resulted in decreased MRP1 level, enhanced drug accumulation and triggered more apoptosis. By contrast, overexpression of SIRT2 in HL60 cells led to increased MRP1 level, drug efflux and attenuated drug sensitivity. Moreover, the decreased expression of phosphorylated ERK1/2 was detected in SIRT2-depleted HL60/A cells and increased expression of phosphorylated ERK1/2 was observed in SIRT2 overexpressed HL60 cells. Furthermore, blockage of ERK1/2 signaling pathway with the chemical inhibitor PD98059, further induced apoptosis of HL60/A cells conferred by SIRT2 depletion. Importantly, ERK1/2 inhibition was able to reverse the drug resistance of HL60 conferred by SIRT2 overexpression. Thus, our findings collectively suggested that the expression level of SIRT2 has a positive relationship with DNR/Ara-C resistance and activity of ERK1/2 signaling pathway. SIRT2 might regulate DNR/Ara-C sensitivity in AML cells at least partially through the ERK1/2 pathway.

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1	Löwenberg B, Downing JR and Burnett A: Acute myeloid leukemia. N Engl J Med. 341:1051–1062. 1999. View Article : Google Scholar : PubMed/NCBI
2	Estey E and Döhner H: Acute myeloid leukaemia. Lancet. 368:1894–1907. 2006. View Article : Google Scholar : PubMed/NCBI
3	DiNardo CD and Cortes JE: New treatment for acute myelogenous leukemia. Expert Opin Pharmacother. 16:95–106. 2015. View Article : Google Scholar
4	Vyas P, Appelbaum FR and Craddock C: Allogeneic hematopoietic cell transplantation for acute myeloid leukemia. Biol Blood Marrow Transplant. 21:8–15. 2015. View Article : Google Scholar
5	Ross DD: Novel mechanisms of drug resistance in leukemia. Leukemia. 14:467–473. 2000. View Article : Google Scholar : PubMed/NCBI
6	Legrand O, Zittoun R and Marie JP: Role of MRP1 in multidrug resistance in acute myeloid leukemia. Leukemia. 13:578–584. 1999. View Article : Google Scholar : PubMed/NCBI
7	Niewiarowski W, Gendaszewska E, Rebowski G, Wójcik M, Mikołajczyk B, Goss W, Soszyński M and Bartosz G: Multidrug resistance-associated protein - reduction of expression in human leukaemia cells by antisense phosphorothioate olignucleotides. Acta Biochim Pol. 47:1183–1188. 2000.
8	Li Z, Xie QR, Chen Z, Lu S and Xia W: Regulation of SIRT2 levels for human non-small cell lung cancer therapy. Lung Cancer. 82:9–15. 2013. View Article : Google Scholar : PubMed/NCBI
9	Harting K and Knöll B: SIRT2-mediated protein deacetylation: An emerging key regulator in brain physiology and pathology. Eur J Cell Biol. 89:262–269. 2010. View Article : Google Scholar
10	Guarente L: Frankin H. Epstein Lecture: Sirtuins, aging, and medicine. N Engl J Med. 364:2235–2244. 2011. View Article : Google Scholar : PubMed/NCBI
11	Peck B, Chen CY, Ho KK, Di Fruscia P, Myatt SS, Coombes RC, Fuchter MJ, Hsiao CD and Lam EW: SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol Cancer Ther. 9:844–855. 2010. View Article : Google Scholar : PubMed/NCBI
12	Audrito V, Vaisitti T, Rossi D, Gottardi D, D'Arena G, Laurenti L, Gaidano G, Malavasi F and Deaglio S: Nicotinamide blocks proliferation and induces apoptosis of chronic lymphocytic leukemia cells through activation of the p53/miR-34a/SIRT1 tumor suppressor network. Cancer Res. 71:4473–4483. 2011. View Article : Google Scholar : PubMed/NCBI
13	Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT, Craddock C and Turner BM: Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia. 19:1751–1759. 2005. View Article : Google Scholar : PubMed/NCBI
14	Li L, Wang L, Li L, Wang Z, Ho Y, McDonald T, Holyoake TL, Chen W and Bhatia R: Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell. 21:266–281. 2012. View Article : Google Scholar : PubMed/NCBI
15	North BJ and Verdin E: Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis. PLoS One. 2:e7842007. View Article : Google Scholar : PubMed/NCBI
16	Sunami Y, Araki M, Hironaka Y, Morishita S, Kobayashi M, Liew EL, Edahiro Y, Tsutsui M, Ohsaka A and Komatsu N: Inhibition of the NAD-dependent protein deacetylase SIRT2 induces granulocytic differentiation in human leukemia cells. PLoS One. 8:e576332013. View Article : Google Scholar : PubMed/NCBI
17	Wang F, Nguyen M, Qin FX and Tong Q: SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell. 6:505–514. 2007. View Article : Google Scholar : PubMed/NCBI
18	Hiratsuka M, Inoue T, Toda T, Kimura N, Shirayoshi Y, Kamitani H, Watanabe T, Ohama E, Tahimic CG, Kurimasa A, et al: Proteomics-based identification of differentially expressed genes in human gliomas: Down-regulation of SIRT2 gene. Biochem Biophys Res Commun. 309:558–566. 2003. View Article : Google Scholar : PubMed/NCBI
19	McGlynn LM, Zino S, MacDonald AI, Curle J, Reilly JE, Mohammed ZM, McMillan DC, Mallon E, Payne AP, Edwards J, et al: SIRT2: Tumour suppressor or tumour promoter in operable breast cancer? Eur J Cancer. 50:290–301. 2014. View Article : Google Scholar
20	Chen J, Chan AW, To KF, Chen W, Zhang Z, Ren J, Song C, Cheung YS, Lai PB, Cheng SH, et al: SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B/glycogen synthase kinase-3β/β-catenin signaling. Hepatology. 57:2287–2298. 2013. View Article : Google Scholar : PubMed/NCBI
21	Jin W, Li Q, Lin Y, Lu Y, Li H, Wang L, Hu R, Ma L, Wang J and Pang T: Reversal of Imatinib resistance in BCR-ABL-positive leukemia after inhibition of the Na⁺/H⁺ exchanger. Cancer Lett. 308:81–90. 2011. View Article : Google Scholar : PubMed/NCBI
22	Kang MA, Kim MS, Kim JY, Shin YJ, Song JY and Jeong JH: A novel pyrido-thieno-pyrimidine derivative activates p53 through induction of phosphorylation and acetylation in colorectal cancer cells. Int J Oncol. 46:342–350. 2015.
23	Konopleva M, Tari AM, Estrov Z, Harris D, Xie Z, Zhao S, López-Berestein G and Andreeff M: Liposomal Bcl-2 antisense oligonucleotides enhance proliferation, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins. Blood. 95:3929–3938. 2000.PubMed/NCBI
24	Matsushita N, Takami Y, Kimura M, Tachiiri S, Ishiai M, Nakayama T and Takata M: Role of NAD-dependent deacetylases SIRT1 and SIRT2 in radiation and cisplatin-induced cell death in vertebrate cells. Genes Cells. 10:321–332. 2005. View Article : Google Scholar : PubMed/NCBI
25	Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P and Reinberg D: Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell. 16:93–105. 2004. View Article : Google Scholar : PubMed/NCBI
26	Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA and Mayo MW: Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23:2369–2380. 2004. View Article : Google Scholar : PubMed/NCBI
27	Nakagawa T and Guarente L: Sirtuins at a glance. J Cell Sci. 124:833–838. 2011. View Article : Google Scholar : PubMed/NCBI
28	North BJ and Verdin E: Mitotic regulation of SIRT2 by cyclin-dependent kinase 1-dependent phosphorylation. J Biol Chem. 282:19546–19555. 2007. View Article : Google Scholar : PubMed/NCBI
29	Dan L, Klimenkova O, Klimiankou M, Klusman JH, van den Heuvel-Eibrink MM, Reinhardt D, Welte K and Skokowa J: The role of sirtuin 2 activation by nicotinamide phosphoribosyl-transferase in the aberrant proliferation and survival of myeloid leukemia cells. Haematologica. 97:551–559. 2012. View Article : Google Scholar :
30	Vousden KH and Lane DP: p53 in health and disease. Nat Rev Mol Cell Biol. 8:275–283. 2007. View Article : Google Scholar : PubMed/NCBI
31	Moll UM, Wolff S, Speidel D and Deppert W: Transcription-independent pro-apoptotic functions of p53. Curr Opin Cell Biol. 17:631–636. 2005. View Article : Google Scholar : PubMed/NCBI
32	Cory S and Adams JM: The Bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer. 2:647–656. 2002. View Article : Google Scholar : PubMed/NCBI
33	Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, Chernov MV and Gudkov AV: A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science. 285:1733–1737. 1999. View Article : Google Scholar : PubMed/NCBI
34	Ali I, Damdimopoulou P, Stenius U and Halldin K: Cadmium at nanomolar concentrations activates Raf-MEK-ERK1/2 MAPKs signaling via EGFR in human cancer cell lines. Chem Biol Interact. 231:44–52. 2015. View Article : Google Scholar : PubMed/NCBI