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Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

Sp1 and c-Myc modulate drug resistance of leukemia stem cells by regulating survivin expression through the ERK-MSK MAPK signaling pathway

Authors: Yi Zhang, Hai-xuan Chen, Shu-yan Zhou, Shao-xiang Wang, Kai Zheng, Dan-dan Xu, Yu-ting Liu, Xiao-yan Wang, Xiao Wang, Hai-zhao Yan, Li Zhang, Qiu-ying Liu, Wan-qun Chen, Yi-fei Wang

Published in: Molecular Cancer | Issue 1/2015

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Abstract

Background

Acute myeloid leukemia (AML) is initiated and maintained by a subset of self-renewing leukemia stem cells (LSCs), which contribute to the progression, recurrence and therapeutic resistance of leukemia. However, the mechanisms underlying the maintenance of LSCs drug resistance have not been fully defined. In this study, we attempted to elucidate the mechanisms of LSCs drug resistance.

Methods

We performed reverse phase protein arrays to analyze the expression of anti-apoptotic proteins in the LSC-enriched leukemia cell line KG-1a. Immuno-blotting, cell viability and clinical AML samples were evaluated to verify the micro-assay results. The characteristics and transcriptional regulation of survivin were analyzed with the relative luciferase reporter assay, mutant constructs, chromatin immuno-precipitation (ChIP), quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR), and western blotting. The levels of Sp1, c-Myc, phospho-extracellular signal-regulated kinase (p-ERK), phospho-mitogen and stress-activated protein kinase (p-MSK) were investigated in paired CD34+ and CD34- AML patient samples.

Results

Survivin was highly over-expressed in CD34 + CD38- KG-1a cells and paired CD34+ AML patients compared with their differentiated counterparts. Functionally, survivin contributes to the drug resistance of LSCs, and Sp1 and c-Myc concurrently regulate levels of survivin transcription. Clinically, Sp1 and c-Myc were significantly up-regulated and positively correlated with survivin in CD34+ AML patients. Moreover, Sp1 and c-Myc were further activated by the ERK/MSK mitogen-activated protein kinase (MAPK) signaling pathway, modulating survivin levels.

Conclusion

Our findings demonstrated that ERK/MSK/Sp1/c-Myc axis functioned as a critical regulator of survivin expression in LSCs, offering a potential new therapeutic strategy for LSCs therapy.
Appendix
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Literature
1.
Creutzig U, Gibson B, Dworzak MN, Adachi S, Kinoshita A. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood. 2012;120:205–3187.CrossRef
2.
Pession A, Masetti R, Rizzari MC Putti C, Casale F, Fagioli F, Luciani M, et al. Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia. Blood. 2013;122:170–8.CrossRefPubMed
3.
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8.CrossRefPubMed
4.
Blair A, Hogge DE, Ailles LE, Lansdorp PM, Sutherland HJ. Lack of expression of Thy-1 (CD90) on acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo. Blood. 1997;89:3104–12.PubMed
5.
6.
Fernandez JG, Rodriguez DA, Valenzuela M, Calderon C, Urzua U, Munroe D, et al. Survivin expression promotes VEGF-induced tumor angiogenesis via PI3K/Akt enhanced beta-catenin/Tcf-Lef dependent transcription. Mol Cancer. 2014;13:209.CrossRefPubMedCentralPubMed
7.
Ji Z, Kumar R, Taylor M, Rajadurai A, Marzuka-Alcala A, Chen YE, et al. Vemurafenib synergizes with nutlin-3 to deplete survivin and suppresses melanoma viability and tumor growth. Clin Cancer Res. 2013;19:4383–91.CrossRefPubMedCentralPubMed
8.
Liu S, Qi L, Yu Q, Song Y, Han W, Zu X, et al. Survivin and HLA-I expression predicts survival of patients with clear cell renal cell carcinoma. Tumour Biol. 2014;35:8281–8.CrossRefPubMed
9.
Van der Waal MS, Hengeveld RC, van der Horst A, Lens SM. Cell division control by the Chromosomal Passenger Complex. Exp Cell Res. 2012;318:1407–20.CrossRefPubMed
10.
Hu D, Liu S, Shi L, Li C, Wu L, Fan Z. Cleavage of survivin by Granzyme M triggers degradation of the survivin-X-linked inhibitor of apoptosis protein (XIAP) complex to free caspase activity leading to cytolysis of target tumor cells. J Biol Chem. 2010;285:18326–35.PubMedCentralPubMed
11.
Chettiar SN, Cooley JV, Park IH, Bhasin D, Chakravarti A, Li PK, et al. Design, synthesis and biological studies of survivin dimerization modulators that prolong mitotic cycle. Bioorg Med Chem Lett. 2013;23:5429–33.CrossRefPubMed
12.
Chu Y, Yao PY, Wang W, Wang D, Wang Z, Zhang L, et al. Aurora B kinase activation requires survivin priming phosphorylation by PLK1. J Mol Cell Biol. 2011;3:260–7.CrossRefPubMedCentralPubMed
13.
Chakrabarty A, Bhola NE, Sutton C, Ghosh R, Kuba MG, Dave B, et al. Trastuzumab-resistant cells rely on a HER2-PI3K-FoxO-survivin axis and are sensitive to PI3K inhibitors. Cancer Res. 2013;73:1190–200.CrossRefPubMedCentralPubMed
14.
Lai YJ, Lin CI, Wang CL, Chao JI. Expression of survivin and p53 modulates honokiol-induced apoptosis in colorectal cancer cells. J Cell Biochem. 2014;115:1888–99.PubMed
15.
Takezawa K, Okamoto I, Nishio K, Janne PA, Nakagawa K. Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer. Clin Cancer Res. 2011;17:2140–8.CrossRefPubMed
16.
Gang EJ, Park E, Gang EJ, Hsieh YT, Schaefer P, Chae S, et al. Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia. Blood. 2011;118:2191–9.CrossRefPubMedCentralPubMed
17.
Fukuda S, Singh P, Moh A, Abe M, Conway EM, Boswell HS, et al. Survivin mediates aberrant hematopoietic progenitor cell proliferation and acute leukemia in mice induced by internal tandem duplication of Flt3. Blood. 2009;114:394–403.CrossRefPubMedCentralPubMed
18.
Guo Y, Mantel C, Hromas RA, Broxmeyer HE. Oct-4 is critical for survival/antiapoptosis of murine embryonic stem cells subjected to stress: effects associated with Stat3/survivin. Stem Cells. 2008;26:30–4.CrossRefPubMedCentralPubMed
19.
20.
Wang F, Wang XK, Shi CJ, Zhang H, Chen YF, Fu LW. Nilotinib enhances the efficacy of conventional chemotherapeutic drugs in CD34(+)CD38(-) stem cells and ABC transporter overexpressing leukemia cells. Molecules. 2014;19:3356–75.CrossRefPubMed
21.
Figueiredo-Pontes LL, Pintao MC, Oliveira LC, Dalmazzo LF, Jacomo RH, Garcia AB, et al. Determination of P-glycoprotein, MDR-related protein 1, breast cancer resistance protein, and lung-resistance protein expression in leukemic stem cells of acute myeloid leukemia. Cytometry B Clin Cytom. 2008;74:163–8.CrossRefPubMed
22.
Laberge RM, Ambadipudi R, Georges E. P-glycoprotein (ABCB1) modulates collateral sensitivity of a multidrug resistant cell line to verapamil. Arch Biochem Biophys. 2009;491:53–60.CrossRefPubMed
23.
Ye Q, Cai W, Zheng Y, Evers BM, She QB. ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer. Oncogene. 2014;33:1828–39.CrossRefPubMedCentralPubMed
24.
Shoeneman JK, Ehrhart EJ, Eickhoff JC, Charles JB, Powers BE, Thamm DH. Expression and function of survivin in canine osteosarcoma. Cancer Res. 2012;72:249–59.CrossRefPubMed
25.
Chou TC. Combined treatment of pancreatic cancer with mithramycin a and tolfenamic Acid promotes sp1 degradation and synergistic antitumor activity--letter. Cancer Res. 2011;71:2794–800.CrossRef
26.
Chu S. Transcriptional regulation by post-transcriptional modification–role of phosphorylation in Sp1 transcriptional activity. Gene. 2012;508:1–8.CrossRefPubMed
27.
Witte KE, Ahlers J, Schafer I, Andre M, Kerst G, Scheel-Walter HG, et al. High proportion of leukemic stem cells at diagnosis is correlated with unfavorable prognosis in childhood acute myeloid leukemia. Pediatr Hematol Oncol. 2011;28:91–9.CrossRefPubMed
28.
Nakahara T, Kita A, Yamanaka K, Mori M, Amino N, Takeuchi M, et al. YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res. 2007;67:8014–21.CrossRefPubMed
29.
Kwee JK, Luque DG, Ferreira AC, Vasconcelos FC, Silva KL, Klumb CE, et al. Modulation of reactive oxygen species by antioxidants in chronic myeloid leukemia cells enhances imatinib sensitivity through survivin downregulation. Anticancer Drugs. 2008;19:975–81.CrossRefPubMed
30.
Liu GX, Li YQ, Huang XR, Wei L, Chen HY, Shi YJ, et al. Disruption of Smad7 promotes ANG II-mediated renal inflammation and fibrosis via Sp1-TGF-beta/Smad3-NF.kappaB-dependent mechanisms in mice. PLoS One. 2013;8:53573–7.CrossRef
31.
Sung WJ, Kim KH, Kim YJ, Chang YC, Lee IH, Park KK. Antifibrotic effect of synthetic Smad/Sp1 chimeric decoy oligodeoxynucleotide through the regulation of epithelial mesenchymal transition in unilateral ureteral obstruction model of mice. Exp Mol Pathol. 2013;95:136–43.CrossRefPubMed
32.
Jiang NY, Woda BA, Banner BF, Whalen GF, Dresser KA, Lu D. Sp1, a new biomarker that identifies a subset of aggressive pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev. 2008;17:1648–52.CrossRefPubMed
33.
McKelvey L, Gutierrez H, Nocentini G, Crampton SJ, Davies AM, CR Riccardi W, et al. The intracellular portion of GITR enhances NGF-promoted neurite growth through an inverse modulation of Erk and NF-kappaB signalling. Biol Open. 2012;1:1016–23.CrossRefPubMedCentralPubMed
34.
Wang KZ, Zhu J, Dagda RK, Uechi G, Cherra 3rd SJ, Gusdon AM, et al. ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: implications for Parkinson’s disease. Mitochondrion. 2014;17:132–40.CrossRefPubMedCentralPubMed
35.
Shi R, Lin J, Guo Y, Gong YP. The MEK1/2 inhibitor U0126 reverses imatinib resistance through down-regulating activation of Lyn/ERK signaling pathway in imatinib-resistant K562R leukemia cells. Pharmazie. 2014;69:346–52.PubMed
36.
Delaney J, Chiarello R, Villar D, Kandalam U, Castejon AM, Clark MA. Regulation of c-fos, c-jun and c-myc gene expression by angiotensin II in primary cultured rat astrocytes: role of ERK1/2 MAP kinases. Neurochem Res. 2008;33:545–50.CrossRefPubMed
37.
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.CrossRefPubMed
38.
Fusello A, Horowitz J, Yang-Iott K, Brady BL, Yin B, Rowh MA, et al. Histone H2AX suppresses translocations in lymphomas of Emu-c-Myc transgenic mice that contain a germline amplicon of tumor-promoting genes. Cell Cycle. 2013;12:2867–75.CrossRefPubMedCentralPubMed
39.
Sankar N, Kadeppagari RK, Thimmapaya B. c-Myc-induced aberrant DNA synthesis and activation of DNA damage response in p300 knockdown cells. J Biol Chem. 2009;284:15193–205.CrossRefPubMedCentralPubMed
40.
Long GV, Fung C, Menzies AM, Pupo GM, Carlino MS, Hyman J, et al. Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat Commun. 2014;5:5694–5.CrossRefPubMed
41.
Al-Huseini LM, Aw Yeang HX, Sethu S, Alhumeed N, Hamdam JM, Tingle Y, et al. Nuclear factor-erythroid 2 (NF-E2) p45-related factor-2 (Nrf2) modulates dendritic cell immune function through regulation of p38 MAPK-cAMP-responsive element binding protein/activating transcription factor 1 signaling. J Biol Chem. 2013;288:22281–8.CrossRefPubMedCentralPubMed
42.
Siebel A, Cubillos-Rojas M, Santos RC, Schneider T, Bonan CD, Bartrons R, et al. Contribution of S6K1/MAPK signaling pathways in the response to oxidative stress: activation of RSK and MSK by hydrogen peroxide. PLoS One. 2013;8:75523–5.CrossRef
43.
Ounzain S, Bowen S, Patel C, Fujita R, Heads RJ, Budhram-Mahadeo VS. Proliferation-associated POU4F2/Brn-3b transcription factor expression is regulated by oestrogen through ERalpha and growth factors via MAPK pathway. Breast Cancer Res. 2011;13:345–9.CrossRef
Metadata
Title
Sp1 and c-Myc modulate drug resistance of leukemia stem cells by regulating survivin expression through the ERK-MSK MAPK signaling pathway
Authors
Yi Zhang
Hai-xuan Chen
Shu-yan Zhou
Shao-xiang Wang
Kai Zheng
Dan-dan Xu
Yu-ting Liu
Xiao-yan Wang
Xiao Wang
Hai-zhao Yan
Li Zhang
Qiu-ying Liu
Wan-qun Chen
Yi-fei Wang
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-015-0326-0

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