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The XIAP inhibitor Embelin enhances TRAIL-induced apoptosis in human leukemia cells by DR4 and DR5 upregulation

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Tumor Biology

Abstract

The present study was designed to explore the effects of low-toxicity Embelin on TRAIL-induced apoptosis and its possible mechanism in human leukemia cells. Our study showed that low-toxicity Embelin enhanced TRAIL-induced apoptosis through DR4 and DR5 upregulation and caspase activation in HL-60 cells. Pan-caspase inhibitor Z-VAD-FMK inhibited cell apoptosis induced by TRAIL alone or combined with low-toxicity Embelin, which indicated the cytotoxic effect is mediated by caspase-dependent apoptosis. Although Embelin is an X chromosome-linked inhibitor-of-apoptosis protein (XIAP) inhibitor, an XIAP independent effect on cell death was detected in HL-60 cells exposed to low-toxicity Embelin and TRAIL. Low-toxicity Embelin upregulated DR4 and DR5 expression to enhance TRAIL-induced apoptosis. The sensitizing effects of Embelin on TRAIL-induced apoptosis were markedly attenuated when DR4/DR5 was knocked down. These data suggested that low-toxicity Embelin enhanced TRAIL-induced cell apoptosis through DR4 and DR5 upregulation, indicating that combination of low-toxicity Embelin and TRAIL may become as a potential antileukemia strategy.

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References

  1. Wiezorek J, Holland P, Graves J. Death receptor agonists as a targeted therapy for cancer. Clin Cancer Res. 2010;16:1701–8.

    Article  CAS  PubMed  Google Scholar 

  2. Schneider P, Olson D, Tardivel A, Browning B, Lugovskoy A, Gong D, et al. Identification of a new murine tumor necrosis factor receptor locus that contains two novel murine receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). J Biol Chem. 2003;278:5444–54.

    Article  CAS  PubMed  Google Scholar 

  3. Kelley SK, Ashkenazi A. Targeting death receptors in cancer with Apo2L/TRAIL. Curr Opin Pharmacol. 2004;4:333–9.

    Article  CAS  PubMed  Google Scholar 

  4. Oldenhuis CN, Stegehuis JH, Walenkamp AM, de Jong S, de Vries EG. Targeting TRAIL death receptors. Curr Opin Pharmacol. 2008;8(4):433–9.

    Article  CAS  PubMed  Google Scholar 

  5. Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998;273:14363–7.

    Article  CAS  PubMed  Google Scholar 

  6. Di X, Zhang G, Zhang Y, Takeda K, Rosado LA, Zhang B. Accumulation of autophagosomes in breast cancer cells induces TRAIL resistance through downregulation of surface expression of death receptors 4 and 5. Oncotarget. 2013;4(9):1349–64.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Morizot A, Mérino D, Lalaoui N, Jacquemin G, Granci V, Iessi E, et al. Chemotherapy overcomes TRAIL-R4-mediated TRAIL resistance at the DISC level. Cell Death Differ. 2011;18(4):700–11.

    Article  CAS  PubMed  Google Scholar 

  8. Lemke J, von Karstedt S, Abd El Hay M, Conti A, Arce F, Montinaro A, et al. Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1. Cell Death Differ. 2014;21(3):491–502.

    Article  CAS  PubMed  Google Scholar 

  9. Allensworth JL, Aird KM, Aldrich AJ, Batinic-Haberle I, Devi GR. XIAP inhibition and generation of reactive oxygen species enhances TRAIL sensitivity in inflammatory breast cancer cells. Mol Cancer Ther. 2012;11(7):1518–27.

    Article  CAS  PubMed  Google Scholar 

  10. Ahn KS, Sethi G, Aggarwal BB. Embelin, an inhibitor of X chromosome-linked inhibitor-of- apoptosis protein, blocks nuclear factor-kappaB (NF-kappaB) signaling pathway leading to suppression of NF-kappaB-regulated antiapoptotic and metastatic geneproducts. Mol Pharmacol. 2007;71:209–19.

    Article  CAS  PubMed  Google Scholar 

  11. Hu R, Zhu K, Li Y, Yao K, Zhang R, Wang H, et al. Embelin induces apoptosis through down-regulation of XIAP in human leukemia cells. Med Oncol. 2011;28:1584–8.

    Article  CAS  PubMed  Google Scholar 

  12. Lee YJ, Seol JW, Jeong JK, Moon MH, Park SY. Inhibition of the ubiquitin-proteasome system sensitizes TRAIL-resistant prostate cancer cells by up-regulation of death receptor 5. Mol Med Rep. 2011;4:1255–9.

    CAS  PubMed  Google Scholar 

  13. Vaculova A, Kaminskyy V, Jalalvand E, Surova O, Zhivotovsky B. Doxorubicin and etoposide sensitize small cell lung carcinoma cells expressing caspase-8 to TRAIL. Mol Cancer. 2010;9:87.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ding L, Yuan C, Wei F, Wang G, Zhang J, Bellail AC, et al. Cisplatin restores TRAIL apoptotic pathway in glioblastoma-derived stem cells through up-regulation of DR5 and down-regulation of c-FLIP. Cancer Investig. 2011;29:511–20.

    Article  CAS  Google Scholar 

  15. Su L, Liu G, Hao X, Zhong N, Zhong D, Liu X, et al. Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells. Eur J Cancer. 2011;47:2471–8.

    Article  CAS  PubMed  Google Scholar 

  16. Mori T, Doi R, Kida A, Nagai K, Kami K, Ito D, et al. Effect of the XIAP inhibitor Embelin on TRAIL-induced apoptosis of pancreatic cancer cells. J Surg Res. 2007;142(2):281–6.

    Article  CAS  PubMed  Google Scholar 

  17. Jiang L, Hao JL, Jin ML, Zhang YG, Wei P. Effect of Embelin on TRAIL receptor 2 mAb-induced apoptosis of TRAIL-resistant A549 non-small cell lung cancer cells. Asian Pac J Cancer Prev. 2013;14(10):6115–20.

    Article  PubMed  Google Scholar 

  18. Matte I, Lane D, Boivin M, Rancourt C, Piché A. MUC16 mucin (CA125) attenuates TRAIL-induced apoptosis by decreasing TRAIL receptor R2 expression and increasing c-FLIP expression. BMC Cancer. 2014;14(1):234.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Siegelin MD, Gaiser T, Siegelin Y. The XIAP inhibitor Embelin enhances TRAIL-mediated apoptosis in malignant glioma cells by down-regulation of the short isoform of FLIP. Neurochem Int. 2009;55(6):423–30.

    Article  CAS  PubMed  Google Scholar 

  20. Liu X, Yue P, Khuri FR, Sun SY. Decoy receptor 2 (DcR2) is a p53 target gene and regulates chemosensitivity. Cancer Res. 2005;65(20):9169–75.

    Article  CAS  PubMed  Google Scholar 

  21. Cheng J, Hylander BL, Baer MR, Chen X, Repasky EA. Multiple mechanism underlie resistance of leukemia cells to Apo2 Ligand/TRAIL. Mol Cancer Ther. 2006;5:1844–53.

    Article  CAS  PubMed  Google Scholar 

  22. Hersey P, Zhang XD. Overcoming resistance of cancer cells to apoptosis. J Cell Physiol. 2003;196:9–18.

    Article  CAS  PubMed  Google Scholar 

  23. Wu B, Wang X, Chi ZF, Hu R, Zhang R, Yang W, et al. Ursolic acid-induced apoptosis in K562 cells involving upregulation of PTEN gene expression and inactivation of the PI3K/Akt pathway. Arch Pharm Res. 2012;35:543–8.

    Article  CAS  PubMed  Google Scholar 

  24. Wang S, El-Deiry WS. Requirement of p53 targets in chemosensitization of colonic carcinoma to death ligand therapy. Proc Natl Acad Sci U S A. 2003;100:15095–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zou W, Liu X, Yue P, Zhou Z, Sporn MB, Lotan R, et al. C-Jun NH2-terminal kinase-mediated up-regulation of death receptor 5 contributes to induction of apoptosis by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1, 9-dien-28-oate in human lung cancer cells. Cancer Res. 2004;64:7570–8.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology, Shengjing Hospital, China Medical University, Shenyang, 110004, Liaoning, China

    Rong Hu, Ying Yang, Zhuogang Liu, Huinan Jiang, Ke Zhu, Jia Li & Wenhui Xu

Authors
  1. Rong Hu
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  2. Ying Yang
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  3. Zhuogang Liu
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  4. Huinan Jiang
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  5. Ke Zhu
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  6. Jia Li
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  7. Wenhui Xu
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Correspondence to Zhuogang Liu.

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© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

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Hu, R., Yang, Y., Liu, Z. et al. The XIAP inhibitor Embelin enhances TRAIL-induced apoptosis in human leukemia cells by DR4 and DR5 upregulation. Tumor Biol. 36, 769–777 (2015). https://doi.org/10.1007/s13277-014-2702-6

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  • DOI: https://doi.org/10.1007/s13277-014-2702-6

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