Induction of the DNA damage response by IAP inhibition triggers natural immunity via upregulation of NKG2D ligands in Hodgkin lymphoma in vitro
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Maike Sauer
, Katrin S. Reiners , Hinrich P. Hansen , Andreas Engert , Stephan Gasser und Elke Pogge von Strandmann
Abstract
Evasion of apoptosis is a hallmark of cancer cells. Inhibitor of apoptosis proteins (IAPs) act as endogenous inhibitors of programmed cell death and are overexpressed in several tumors including Hodgkin lymphoma (HL). Preclinical studies indicate antitumor activity of IAP antagonists and clinical studies in hematological malignancies are underway. Here, we investigate the impact of the small molecule IAP antagonist LCL161 on HL cell lines. Although the antagonist caused rapid degradation of cIAP1 leading to TNFα secretion, LCL161 did not promote apoptosis significantly. However, LCL161 induced expression of MICA and MICB, ligands for the activating immune receptor NKG2D, and enhanced the susceptibility of HL cells to NKG2D-dependent lysis by NK cells. MICA/B upregulation was dependent on activation of the DNA damage response upon LCL161 treatment. Taken together, we demonstrate a novel link between IAP inhibition, DNA damage and immune recognition.
We are deeply grateful to the Deutsche Krebshilfe (grant 109751 to EPvS) and the Deutsche Forschungsgemeinschaft (KFO286, Z4 to EPvS) for generous funding of this study. LCL161 was kindly provided by Novartis.
Conflict of interest statement
Author’s Conflict of interest disclosure: The authors report no potential conflicts of interest.
References
Akyurek, N., Ren, Y., Rassidakis, G.Z., Schlette, E.J., and Medeiros, L.J. (2006). Expression of inhibitor of apoptosis proteins in B-cell non-Hodgkin and Hodgkin lymphomas. Cancer 107, 1844–1851.10.1002/cncr.22219Suche in Google Scholar PubMed
Armeanu, S., Bitzer, M., Lauer, U.M., Venturelli, S., Pathil, A., Krusch, M., Kaiser, S., Jobst, J., Smirnow, I., Wagner, A., et al. (2005). Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res. 65, 6321–6329.10.1158/0008-5472.CAN-04-4252Suche in Google Scholar PubMed
Bauer, S., Groh, V., Wu, J., Steinle, A., Phillips, J.H., Lanier, L.L., and Spies, T. (1999). Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285, 727–729.10.1126/science.285.5428.727Suche in Google Scholar PubMed
Boll, B., Eltaib, F., Reiners, K.S., von Tresckow, B., Tawadros, S., Simhadri, V.R., Burrows, F.J., Lundgren, K., Hansen, H.P., Engert, A., et al. (2009). Heat shock protein 90 inhibitor BIIB021 (CNF2024) depletes NF-kappaB and sensitizes Hodgkin’s lymphoma cells for natural killer cell-mediated cytotoxicity. Clin. Cancer Res. 15, 5108–5116.10.1158/1078-0432.CCR-09-0213Suche in Google Scholar PubMed
Boll, B., Hansen, H., Heuck, F., Reiners, K., Borchmann, P., Rothe, A., Engert, A., and Pogge von Strandmann, E. (2005). The fully human anti-CD30 antibody 5F11 activates NF-{kappa}B and sensitizes lymphoma cells to bortezomib-induced apoptosis. Blood 106, 1839–1842.10.1182/blood-2005-01-0427Suche in Google Scholar PubMed
Chen, K.F., Lin, J.P., Shiau, C.W., Tai, W.T., Liu, C.Y., Yu, H.C., Chen, P.J., and Cheng, A.L. (2012). Inhibition of Bcl-2 improves effect of LCL161, a SMAC mimetic, in hepatocellular carcinoma cells. Biochem. Pharmacol. 84, 268–277.10.1016/j.bcp.2012.04.023Suche in Google Scholar PubMed
Cheung, H.H., Mahoney,D.J., Lacasse, E.C., and Korneluk, R.G. (2009). Down-regulation of c-FLIP enhances death of cancer cells by smac mimetic compound. Cancer Res. 69, 7729–7738.10.1158/0008-5472.CAN-09-1794Suche in Google Scholar PubMed
Cosman, D., Mullberg, J., Sutherland, C.L., Chin, W., Armitage, R., Fanslow, W., Kubin, M., and Chalupny, N.J. (2001). ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14, 123–133.10.1016/S1074-7613(01)00095-4Suche in Google Scholar PubMed
Darding, M. and Meier, P. (2012). IAPs: guardians of RIPK1. Cell Death Differ. 19, 58–66.10.1038/cdd.2011.163Suche in Google Scholar PubMed PubMed Central
Deguine, J., Breart, B., Lemaître, F., and Bousso, P. (2012). Cutting edge: tumor-targeting antibodies enhance NKG2D-mediated NK cell cytotoxicity by stabilizing NK cell-tumor cell interactions. J. Immunol. 189, 5493–5497.10.4049/jimmunol.1202065Suche in Google Scholar PubMed
Deveraux, Q. L. and Reed, J.C. (1999). IAP family proteins–suppressors of apoptosis. Genes Dev 13, 239–252.10.1101/gad.13.3.239Suche in Google Scholar PubMed
Dutton, A., O’Neil, J.D., Milner, A.E., Reynolds, G.M., Starczynski, J., Crocker, J., Young, L.S., and Murray, P.G. (2004). Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin’s lymphoma cells from autonomous Fas-mediated death. Proc. Natl. Acad. Sci. USA 101, 6611–6616.10.1073/pnas.0400765101Suche in Google Scholar PubMed PubMed Central
Gasser, S., Orsulic, S., and Raulet, D.H. (2005). The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190.10.1038/nature03884Suche in Google Scholar PubMed PubMed Central
Gyrd-Hansen, M. and Meier, P. (2010). IAPs: from caspase inhibitors to modulators of NF-kB, inflammation and cancer. Nat. Rev. Cancer 10, 561–574.10.1038/nrc2889Suche in Google Scholar PubMed
Hanahan, D. and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646–674.10.1016/j.cell.2011.02.013Suche in Google Scholar PubMed
Horie, R., Higashihara, M., and Watanabe, T. (2003). Hodgkin’s lymphoma and CD30 signal transduction. Int. J. Hematol. 77, 37–47.10.1007/BF02982601Suche in Google Scholar PubMed
Horie, R., Watanabe, T., Morishita, Y., Ito, K., Ishida, T., Kanegae, Y., Saito, I., Higashihara, M., Mori, S., Kadin, M.E., et al. (2002). Ligand-independent signaling by overexpressed CD30 drives NF-kB activation in Hodgkin-Reed-Sternberg cells. Oncogene 21, 2493–2503.10.1038/sj.onc.1205337Suche in Google Scholar PubMed
Huang, B., Sikorski, R., Sampath, P., and Thorne, S.H. (2011). Modulation of NKG2D-ligand cell surface expression enhances immune cell therapy of cancer. J. Immunother. 34, 289–296.10.1097/CJI.0b013e31820e1b0dSuche in Google Scholar PubMed PubMed Central
Jayanthan, A., Howard, S.C., Trippett, T., Horton, T., Whitlock, J.A., Daisley, L., Lewis, V., and Narendran, A. (2009). Targeting the Bcl-2 family of proteins in Hodgkin lymphoma: in vitro cytotoxicity, target modulation and drug combination studies of the Bcl-2 homology 3 mimetic ABT-737. Leuk. Lymphoma 50, 1174–1182.10.1080/10428190902943069Suche in Google Scholar PubMed
Jungnickel, B., Staratschek-Jox, A., Braeuninger, A., Spieker, T., Wolf, J., Diehl V., Hansmann M.-L., Rajewsky K., and Kueppers R. (2000). Clonal deleterious mutations in the IkBa gene in the malignant cells in Hodgkin’s lymphoma. J. Exp. Med. 191, 395–402.10.1084/jem.191.2.395Suche in Google Scholar PubMed PubMed Central
Knights, A.J., Fucikova, J., Pasam, A., Koernig, S., and Cebon, J. (2013). Inhibitor of apoptosis protein (IAP) antagonists demonstrate divergent immunomodulatory properties in human immune subsets with implications for combination therapy. Cancer Immunol. Immunother. 62, 321–335.10.1007/s00262-012-1342-1Suche in Google Scholar PubMed
Li, L., Thomas, R.M., Suzuki, H., De Brabander, J.K., Wang, X., and Harran, P.G. (2004). A small molecule Smac mimic potentiates TRAIL- and TNFa-mediated cell death. Science 305, 1471–1474.10.1126/science.1098231Suche in Google Scholar PubMed
Pich, C., Teiti, I., Rochaix, P., Mariamé, B., Couderc, B., Favre, G., and Tilkin-Mariamé, A.F. (2013). Statins reduce melanoma development and metastasis through MICA overexpression. Front. Immunol. 4, 62.10.3389/fimmu.2013.00062Suche in Google Scholar PubMed PubMed Central
Scott, A.M., Wolchok, J.D., and Old, L.J. (2012). Antibody therapy of cancer. Nat. Rev. Cancer 12, 278–287.10.1038/nrc3236Suche in Google Scholar PubMed
Servida, F., Lecis, D., Scavullo, C., Drago, C., Seneci, P., Carlo-Stella, C., Manzoni, L., Polli, E., Lambertenghi Deliliers, G., Delia. D., et al. (2011). Novel second mitochondria-derived activator of caspases (Smac) mimetic compounds sensitize human leukemic cell lines to conventional chemotherapeutic drug-induced and death receptor-mediated apoptosis. Invest. New Drugs 29, 1264–1275.10.1007/s10637-010-9475-6Suche in Google Scholar PubMed
Soriani, A., Zingoni, A., Cerboni, C., Iannitto, M.L., Ricciardi, M.R., Di Gialleonardo, V., Cippitelli, M., Fionda, C., Petrucci, M.T., Guarini, A., et al. (2009). ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113, 3503–3511.10.1182/blood-2008-08-173914Suche in Google Scholar PubMed
Steidl, C., Connors, J.M., and Gascoyne, R.D. (2011). Molecular pathogenesis of Hodgkin’s lymphoma: increasing evidence of the importance of the microenvironment. J. Clin. Oncol. 2, 1812–1826.10.1200/JCO.2010.32.8401Suche in Google Scholar PubMed
Strasser, A., Jost, P.J., and Nagata, S. (2009). The many roles of FAS receptor signaling in the immune system. Immunity 30, 180–192.10.1016/j.immuni.2009.01.001Suche in Google Scholar PubMed PubMed Central
Varfolomeev, E., Blankenship, J.W., Wayson, S.M., Fedorova, A.V., Kayagaki, N., Garg, P., Zobel, K., Dynek, J.N., Elliott, L.O., Wallweber, H.J., et al. (2007). IAP antagonists induce autoubiquitination of c-IAPs, NF-kB activation, and TNFa-dependent apoptosis. Cell 131, 669–681.10.1016/j.cell.2007.10.030Suche in Google Scholar PubMed
Villa-Morales, M. and Fernandez-Piqueras, J. (2012). Targeting the Fas/FasL signaling pathway in cancer therapy. Expert Opin. Ther. Targets 16, 85–101.10.1517/14728222.2011.628937Suche in Google Scholar PubMed
Vince, J.E., Wong, W.W., Khan, N., Feltham, R., Chau, D., Ahmed, A.U., Benetatos, C.A., Chunduru, S.K., Condon, S.M., McKinlay, M., et al. (2007). IAP antagonists target cIAP1 to induce TNFa-dependent apoptosis. Cell 131, 682–693.10.1016/j.cell.2007.10.037Suche in Google Scholar PubMed
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Artikel in diesem Heft
- Masthead
- Masthead
- Reviews
- Endothelial progenitor cells in coronary artery disease
- Current methods for the isolation of extracellular vesicles
- S-glutathionylation: relevance in diabetes and potential role as a biomarker
- Site-directed spin labeling EPR spectroscopy in protein research
- What goes up must come down: molecular basis of MAPKAP kinase 2/3-dependent regulation of the inflammatory response and its inhibition
- Research Articles/Short Communications
- Molecular Medicine
- Effects of selective hypothermia on blood-brain barrier integrity and tight junction protein expression levels after intracerebral hemorrhage in rats
- Induction of the DNA damage response by IAP inhibition triggers natural immunity via upregulation of NKG2D ligands in Hodgkin lymphoma in vitro
- Proteomic analysis of bladder cancer by iTRAQ after Bifidobacterium infantis-mediated HSV-TK/GCV suicide gene treatment
- Cell Biology and Signaling
- Human carbonic anhydrase VII protects cells from oxidative damage
- Proteolysis
- Cathepsin S generates soluble CX3CL1 (fractalkine) in vascular smooth muscle cells