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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

Tenovin-6-mediated inhibition of SIRT1/2 induces apoptosis in acute lymphoblastic leukemia (ALL) cells and eliminates ALL stem/progenitor cells

Authors: Yanli Jin, Qi Cao, Chun Chen, Xin Du, Bei Jin, Jingxuan Pan

Published in: BMC Cancer | Issue 1/2015

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Abstract

Background

Acute lymphoblastic leukemia (ALL) is a heterogeneous group of malignant disorders derived from B- or T-cell lymphoid progenitor cells. ALL often is refractory to or relapses after treatment; thus, novel targeted therapy for ALL is urgently needed. In the present study, we initially found that the level of SIRT1, a class III histone deacetylase, was higher in primary ALL cells from patients than in peripheral blood mononuclear cells from healthy individuals. But it is not clear whether inhibition of SIRT1 by its selective small molecule inhibitor Tenovin-6 is effective against ALL cells.

Methods

We tested the effect of Tenovin-6 on ALL cell lines (REH and NALM-6) and primary cells from 41 children with ALL and 2 adult patients with ALL. The effects of Tenovin-6 on cell viability were determined by MTS assay; colony-forming assays were determined by soft agar in ALL cell lines and methylcellulose medium in normal bone marrow cells and primary ALL blast cells; cell apoptosis and cell cycling were examined by flow cytometry; the signaling pathway was determined by Western blotting; ALL stem/progenitor cells were seperated by using MACS MicroBead kit.

Results

The results showed that Tenovin-6 treatment activated p53, potently inhibited the growth of pre-B ALL cells and primary ALL cells, and sensitized ALL cells to frontline chemotherapeutic agents etoposide and cytarabine. Tenovin-6 induced apoptosis in REH and NALM-6 cells and primary ALL cells and diminished expression of Mcl-1 and X-linked inhibitor of apoptosis protein (XIAP) in such cells. Furthermore, inhibition of SIRT1 by Tenovin-6 inhibited the Wnt/β-catenin signaling pathway and eliminated ALL stem/progenitor (CD133 + CD19-) cells.

Conclusion

Our results indicate that Tenovin-6 may be a promising targeted therapy for ALL and clinical trials are warranted to investigate its efficacy in ALL patients.
Literature
1.
Bhojwani D, Pui CH. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 2013;14(6):e205–217.CrossRefPubMed
2.
August KJ, Narendran A, Neville KA. Pediatric relapsed or refractory leukemia: new pharmacotherapeutic developments and future directions. Drugs. 2013;73(5):439–61.CrossRefPubMed
3.
Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, Lambert J, Beldjord K, Lengline E, et al. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. J Clin Oncol. 2013;31(34):4333–42.CrossRefPubMed
4.
Ferrando AA, Look AT. Gene expression profiling in T-cell acute lymphoblastic leukemia. Semin Hematol. 2003;40(4):274–80.CrossRefPubMed
5.
Papaemmanuil E, Rapado I, Li Y, Potter NE, Wedge DC, Tubio J, et al. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat Genet. 2014;46(2):116–25.CrossRefPubMedPubMedCentral
6.
Chatterton Z, Morenos L, Mechinaud F, Ashley DM, Craig JM, Sexton-Oates A, et al. Epigenetic deregulation in pediatric acute lymphoblastic leukemia. Epigenetics. 2014;9(3):459–67.CrossRefPubMedPubMedCentral
7.
Rangwala S, Zhang C, Duvic M. HDAC inhibitors for the treatment of cutaneous T-cell lymphomas. Future Med Chem. 2012;4(4):471–86.CrossRefPubMed
8.
Hojfeldt JW, Agger K, Helin K. Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov. 2013;12(12):917–30.CrossRefPubMed
9.
Mund C, Lyko F. Epigenetic cancer therapy: Proof of concept and remaining challenges. Bioessays. 2010;32(11):949–57.CrossRefPubMed
10.
Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004;303(5666):2011–5.CrossRefPubMed
11.
Qiang L, Wang H, Farmer SR. Adiponectin secretion is regulated by SIRT1 and the endoplasmic reticulum oxidoreductase Ero1-L alpha. Mol Cell Biol. 2007;27(13):4698–707.CrossRefPubMedPubMedCentral
12.
Kojima K, Ohhashi R, Fujita Y, Hamada N, Akao Y, Nozawa Y, et al. A role for SIRT1 in cell growth and chemoresistance in prostate cancer PC3 and DU145 cells. Biochem Biophys Res Commun. 2008;373(3):423–8.CrossRefPubMed
13.
Liang XJ, Finkel T, Shen DW, Yin JJ, Aszalos A, Gottesman MM. SIRT1 contributes in part to cisplatin resistance in cancer cells by altering mitochondrial metabolism. Mol Cancer Res. 2008;6(9):1499–506.CrossRefPubMedPubMedCentral
14.
Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001;107(2):137–48.CrossRefPubMed
15.
Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 2001;107(2):149–59.CrossRefPubMed
16.
Cohen HY, Lavu S, Bitterman KJ, Hekking B, Imahiyerobo TA, Miller C, et al. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis. Mol Cell. 2004;13(5):627–38.CrossRefPubMed
17.
Nakae J, Cao Y, Daitoku H, Fukamizu A, Ogawa W, Yano Y, et al. The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity. J Clin Invest. 2006;116(9):2473–83.PubMedPubMedCentral
18.
Li L, Wang L, Wang Z, Ho Y, McDonald T, Holyoake TL, et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell. 2012;21(2):266–81.CrossRefPubMedPubMedCentral
19.
Yuan H, Wang Z, Li L, Zhang H, Modi H, Horne D, et al. Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood. 2012;119(8):1904–14.CrossRefPubMedPubMedCentral
20.
Jin Y, Lu Z, Ding K, Li J, Du X, Chen C, et al. Antineoplastic mechanisms of niclosamide in acute myelogenous leukemia stem cells: inactivation of the NF-kappaB pathway and generation of reactive oxygen species. Cancer Res. 2010;70(6):2516–27.CrossRefPubMed
21.
Shi X, Jin Y, Cheng C, Zhang H, Zou W, Zheng Q, et al. Triptolide inhibits Bcr-Abl transcription and induces apoptosis in STI571-resistant chronic myelogenous leukemia cells harboring T315I mutation. Clin Cancer Res. 2009;15(5):1686–97.CrossRefPubMed
22.
Wu Y, Chen C, Sun X, Shi X, Jin B, Ding K, et al. Cyclin-dependent kinase 7/9 inhibitor SNS-032 abrogates FIP1-like-1 platelet-derived growth factor receptor alpha and bcr-abl oncogene addiction in malignant hematologic cells. Clin Cancer Res. 2012;18(7):1966–78.CrossRefPubMed
23.
Zeng G, Apte U, Micsenyi A, Bell A, Monga SP. Tyrosine residues 654 and 670 in beta-catenin are crucial in regulation of Met-beta-catenin interactions. Exp Cell Res. 2006;312(18):3620–30.CrossRefPubMedPubMedCentral
24.
Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, Aoubala M, et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell. 2008;13(5):454–63.CrossRefPubMedPubMedCentral
25.
Nusse R, Fuerer C, Ching W, Harnish K, Logan C, Zeng A, et al. Wnt signaling and stem cell control. Cold Spring Harb Symp Quant Biol. 2008;73:59–66.CrossRefPubMed
26.
Holloway KR, Calhoun TN, Saxena M, Metoyer CF, Kandler EF, Rivera CA, et al. SIRT1 regulates Dishevelled proteins and promotes transient and constitutive Wnt signaling. Proc Natl Acad Sci U S A. 2010;107(20):9216–21.CrossRefPubMedPubMedCentral
27.
28.
Moon BS, Jeong WJ, Park J, Kim TI, Min Do S, Choi KY. Role of Oncogenic K-Ras in Cancer Stem Cell Activation by Aberrant Wnt/beta-Catenin Signaling. J Natl Cancer Inst. 2014;106(2):djt373.CrossRefPubMed
29.
Cox CV, Diamanti P, Evely RS, Kearns PR, Blair A. Expression of CD133 on leukemia-initiating cells in childhood ALL. Blood. 2009;113(14):3287–96.CrossRefPubMed
30.
31.
Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One. 2008;3(4):e2020.CrossRefPubMedPubMedCentral
32.
Heltweg B, Gatbonton T, Schuler AD, Posakony J, Li H, Goehle S, et al. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 2006;66(8):4368–77.CrossRefPubMed
33.
Liu T, Liu PY, Marshall GM. The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer Res. 2009;69(5):1702–5.CrossRefPubMed
34.
Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT, et al. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia. 2005;19(10):1751–9.CrossRefPubMed
35.
Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A, et al. SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res. 2007;67(14):6612–8.CrossRefPubMed
36.
Ozdag H, Teschendorff AE, Ahmed AA, Hyland SJ, Blenkiron C, Bobrow L, et al. Differential expression of selected histone modifier genes in human solid cancers. BMC Genomics. 2006;7:90.CrossRefPubMedPubMedCentral
37.
Hida Y, Kubo Y, Murao K, Arase S. Strong expression of a longevity-related protein, SIRT1, in Bowen's disease. Arch Dermatol Res. 2007;299(2):103–6.CrossRefPubMed
38.
Chu F, Chou PM, Zheng X, Mirkin BL, Rebbaa A. Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1. Cancer Res. 2005;65(22):10183–7.CrossRefPubMed
39.
Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer. 2006;5:67.CrossRefPubMedPubMedCentral
40.
Metadata
Title
Tenovin-6-mediated inhibition of SIRT1/2 induces apoptosis in acute lymphoblastic leukemia (ALL) cells and eliminates ALL stem/progenitor cells
Authors
Yanli Jin
Qi Cao
Chun Chen
Xin Du
Bei Jin
Jingxuan Pan
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1282-1

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