Advertisement

Apoptosis

pp 1–9 | Cite as

NF-κB contributes to Smac mimetic-conferred protection from tunicamycin-induced apoptosis

  • Behnaz Ahangarian Abhari
  • Nicole McCarthy
  • Patrizia Agostinis
  • Simone FuldaEmail author
Article
  • 60 Downloads

Abstract

Smac mimetics that deplete cellular inhibitor of apoptosis (cIAP) proteins have been shown to activate Nuclear Factor-kappa B (NF-κB). Here, we report that Smac mimetic-mediated activation of NF-κB contributes to the rescue of cancer cells from tunicamycin (TM)-triggered apoptosis. The prototypic Smac mimetic BV6 activates non-canonical and canonical NF-κB pathways, while TM has little effect on NF-κB signaling. Importantly, ectopic expression of dominant-negative IκBα superrepressor (IκBα-SR), which inhibits canonical and non-canonical NF-κB activation, significantly reversed this BV6-imposed protection against TM. Similarly, transient or stable knockdown of NF-κB-inducing kinase, which accumulated upon exposure to BV6 alone and in combination with TM, significantly counteracted BV6-mediated inhibition of TM-induced apoptosis. Interestingly, while cIAP2 was initially degraded upon BV6 treatment, it was subsequently upregulated in an NF-κB-dependent manner, as this restoration of cIAP2 expression was abolished in IκBα-SR-overexpressing cells. Interestingly, upon exposure to TM/BV6 apoptosis was significantly increased in cIAP2 knockdown cells. Furthermore, NF-κB inhibition partially prevented BV6-stimulated expression of Mcl-1 upon TM treatment. Consistently, Mcl-1 silencing significantly inhibited BV6-mediated protection from TM-induced apoptosis. Thus, NF-κB activation by Smac mimetic contributes to Smac mimetic-mediated protection against TM-induced apoptosis.

Keywords

Apoptosis Cell death Smac NF-κB Tunicamycin 

Notes

Acknowledgements

We thank Dr. D. Vucic (Genentech Inc., South San Francisco, CA) for providing BV6, Prof. M. Leverkus (Mannheim, Germany) for cIAP1/2 DKO MEFs, and C. Hugenberg for expert secretarial assistance.

Funding

This work has been partially supported by grants from the Deutsche Forschungsgemeinschaft and BMBF (to S.F.). Furthermore, this project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 675448 (to S.F, P.A. and N. McC.). This paper presents research results of the IUAP7/32, funded by the Interuniversity Attraction Poles Program, initiated by the Belgian State, Science Policy Office (to S.F. and P.A.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Lockshin RA, Zakeri Z (2007) Cell death in health and disease. J Cell Mol Med 11:1214–1224.  https://doi.org/10.1111/j.1582-4934.2007.00150.x CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Kim I, Xu W, Reed JC (2008) Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 7:1013–1030.  https://doi.org/10.1038/nrd2755 CrossRefPubMedGoogle Scholar
  3. 3.
    Fulda S (2009) Tumor resistance to apoptosis. Int J Cancer 124:511–515.  https://doi.org/10.1002/ijc.24064 CrossRefPubMedGoogle Scholar
  4. 4.
    Fulda S, Vucic D (2012) Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov 11:109–124.  https://doi.org/10.1038/nrd3627 CrossRefPubMedGoogle Scholar
  5. 5.
    Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallweber HJ, Flygare JA, Fairbrother WJ, Deshayes K, Dixit VM, Vucic D (2007) IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell 131:669–681.  https://doi.org/10.1016/j.cell.2007.10.030 CrossRefPubMedGoogle Scholar
  6. 6.
    Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL, Silke J (2007) IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 131:682–693.  https://doi.org/10.1016/j.cell.2007.10.037 CrossRefPubMedGoogle Scholar
  7. 7.
    Oeckinghaus A, Hayden MS, Ghosh S (2011) Crosstalk in NF-kappaB signaling pathways. Nat Immunol 12:695–708.  https://doi.org/10.1038/ni.2065 CrossRefPubMedGoogle Scholar
  8. 8.
    Nozaki S, Sledge GW Jr, Nakshatri H (2001) Repression of GADD153/CHOP by NF-kappaB: a possible cellular defense against endoplasmic reticulum stress-induced cell death. Oncogene 20:2178–2185.  https://doi.org/10.1038/sj.onc.1204292 CrossRefPubMedGoogle Scholar
  9. 9.
    Fulda S, Sieverts H, Friesen C, Herr I, Debatin KM (1997) The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells. Cancer Res 57:3823–3829PubMedGoogle Scholar
  10. 10.
    Karl S, Pritschow Y, Volcic M, Hacker S, Baumann B, Wiesmuller L, Debatin KM, Fulda S (2009) Identification of a novel pro-apopotic function of NF-kappaB in the DNA damage response. J Cell Mol Med 13:4239–4256.  https://doi.org/10.1111/j.1582-4934.2009.00888.x CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Eckhardt I, Roesler S, Fulda S (2013) Identification of DR5 as a critical, NF-kappaB-regulated mediator of Smac-induced apoptosis. Cell Death Dis 4:e936.  https://doi.org/10.1038/cddis.2013.457 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Geserick P, Hupe M, Moulin M, Wong WW, Feoktistova M, Kellert B, Gollnick H, Silke J, Leverkus M (2009) Cellular IAPs inhibit a cryptic CD95-induced cell death by limiting RIP1 kinase recruitment. J Cell Biol 187:1037–1054.  https://doi.org/10.1083/jcb.200904158 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Xu H, Jiang B, Meng L, Ren T, Zeng Y, Wu J, Qu L, Shou C (2012) N-alpha-acetyltransferase 10 protein inhibits apoptosis through RelA/p65-regulated MCL1 expression. Carcinogenesis 33:1193–1202.  https://doi.org/10.1093/carcin/bgs144 CrossRefPubMedGoogle Scholar
  14. 14.
    Jiang CC, Lucas K, Avery-Kiejda KA, Wade M, deBock CE, Thorne RF, Allen J, Hersey P, Zhang XD (2008) Up-regulation of Mcl-1 is critical for survival of human melanoma cells upon endoplasmic reticulum stress. Cancer Res 68:6708–6717.  https://doi.org/10.1158/0008-5472.CAN-08-0349 CrossRefPubMedGoogle Scholar
  15. 15.
    Petersen SL, Peyton M, Minna JD, Wang X (2010) Overcoming cancer cell resistance to Smac mimetic induced apoptosis by modulating cIAP-2 expression. Proc Natl Acad Sci USA 107:11936–11941.  https://doi.org/10.1073/pnas.1005667107 CrossRefPubMedGoogle Scholar
  16. 16.
    Fritsch RM, Schneider G, Saur D, Scheibel M, Schmid RM (2007) Translational repression of MCL-1 couples stress-induced eIF2 alpha phosphorylation to mitochondrial apoptosis initiation. J Biol Chem 282:22551–22562.  https://doi.org/10.1074/jbc.M702673200 CrossRefPubMedGoogle Scholar
  17. 17.
    Martin-Perez R, Niwa M, Lopez-Rivas A (2012) ER stress sensitizes cells to TRAIL through down-regulation of FLIP and Mcl-1 and PERK-dependent up-regulation of TRAIL-R2. Apoptosis 17:349–363.  https://doi.org/10.1007/s10495-011-0673-2 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Allagnat F, Cunha D, Moore F, Vanderwinden JM, Eizirik DL, Cardozo AK (2011) Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to beta-cell apoptosis. Cell Death Differ 18:328–337.  https://doi.org/10.1038/cdd.2010.105 CrossRefPubMedGoogle Scholar
  19. 19.
    Berger R, Jennewein C, Marschall V, Karl S, Cristofanon S, Wagner L, Vellanki SH, Hehlgans S, Rodel F, Debatin KM, Ludolph AC, Fulda S (2011) NF-{kappa}B is required for Smac mimetic-mediated sensitization of glioblastoma cells for {gamma}-irradiation-induced apoptosis. Mol Cancer Ther 10:1867–1875.  https://doi.org/10.1158/1535-7163.MCT-11-0218 CrossRefPubMedGoogle Scholar
  20. 20.
    Stadel D, Cristofanon S, Abhari BA, Deshayes K, Zobel K, Vucic D, Debatin KM, Fulda S (2011) Requirement of nuclear factor kappaB for Smac mimetic-mediated sensitization of pancreatic carcinoma cells for gemcitabine-induced apoptosis. Neoplasia 13:1162–1170CrossRefGoogle Scholar
  21. 21.
    Wagner L, Marschall V, Karl S, Cristofanon S, Zobel K, Deshayes K, Vucic D, Debatin KM, Fulda S (2013) Smac mimetic sensitizes glioblastoma cells to temozolomide-induced apoptosis in a RIP1- and NF-kappaB-dependent manner. Oncogene 32:988–997.  https://doi.org/10.1038/onc.2012.108 CrossRefPubMedGoogle Scholar
  22. 22.
    Tchoghandjian A, Jennewein C, Eckhardt I, Rajalingam K, Fulda S (2013) Identification of non-canonical NF-kappaB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells. Cell Death Dis 4:e564.  https://doi.org/10.1038/cddis.2013.70 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Tchoghandjian A, Jennewein C, Eckhardt I, Momma S, Figarella-Branger D, Fulda S (2014) Smac mimetic promotes glioblastoma cancer stem-like cell differentiation by activating NF-κB. Cell Death Differ 21:735–747.  https://doi.org/10.1038/cdd.2013.200 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institute for Experimental Cancer Research in PediatricsGoethe-UniversityFrankfurtGermany
  2. 2.German Cancer Consortium (DKTK)HeidelbergGermany
  3. 3.German Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.Cell Death Research and Therapy Unit, Department of Cellular and Molecular MedicineKU LeuvenLeuvenBelgium

Personalised recommendations