Abstract
The transcription factor nuclear factor-kappaB (NF-κB) is a key regulator of stress-induced transcriptional activation and has been implicated in mediating primary or acquired apoptosis resistance in various cancers. In the present study, we therefore investigated the role of NF-κB in regulating apoptosis in malignant glioma, a prototypic tumor refractory to current treatment approaches. Here, we report that constitutive NF-κB DNA-binding activity was low or moderate in eight different glioblastoma cell lines compared to Hodgkin's lymphoma cells, known to harbor aberrant constitutive NF-κB activity. Specific inhibition of NF-κB by overexpression of inhibitor of κB (IκB)α superrepressor did not enhance spontaneous apoptosis of glioblastoma cells. Also, overexpression of IκBα superrepressor had no significant impact on apoptosis induced by two prototypic classes of apoptotic stimuli, that is, chemotherapeutic drugs or death-inducing ligands such as TNF-related apoptosis inducing ligand (TRAIL), which are known to trigger NF-κB activation as part of a cellular stress response. Similarly, inhibition of NF-κB by the proteasome inhibitor MG132 did not increase doxorubicin (Doxo)-induced apoptosis of glioblastoma cells, although it prevented DNA binding of NF-κB complexes in response to Doxo. Interestingly, proteasome inhibition significantly sensitized glioblastoma cells for TRAIL-induced apoptosis. These findings indicate that the characteristic antiapoptotic function of NF-κB reported for many cancers is not a primary feature of glioblastoma and thus, specific NF-κB inhibition may not be effective for chemosensitization of glioblastoma. Instead, proteasome inhibitors, which enhanced TRAIL-induced apoptosis in an NF-κB-independent manner, may open new perspectives to increase the efficacy of TRAIL-based regimens in glioblastoma, which warrants further investigation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Andrews NC, Faller DV . (1991). Nucleic Acids Res 19: 2499.
Baumann B, Bohnenstengel F, Siegmund D, Wajant H, Weber C, Herr I et al. (2002). J Biol Chem 277: 44791–44800.
Bentires-Alj M, Hellin AC, Ameyar M, Chouaib S, Merville MP, Bours V . (1999). Cancer Res 59: 811–815.
Biswas DK, Cruz AP, Gansberger E, Pardee AB . (2000). Proc Natl Acad Sci USA 97: 8542–8547.
Bradford MM . (1976). Anal Biochem 72: 248–254.
Campbell KJ, Rocha S, Perkins ND . (2004). Mol Cell 13: 853–865.
Darnell Jr JE . (2002). Nat Rev Cancer 2: 740–749.
Denk A, Goebeler M, Schmid S, Berberich I, Ritz O, Lindemann D et al. (2001). J Biol Chem. 276: 28451–28458.
Fulda S, Friesen C, Los M, Scaffidi C, Mier W, Benedict M et al. (1997). Cancer Res 57: 4956–4964.
Gurney JG, Kadan-Lottick N . (2001). Curr Opin Oncol 13: 160–166.
Hayashi S, Yamamoto M, Ueno Y, Ikeda K, Ohshima K, Soma G et al. (2001). Neurol Med Chir (Tokyo) 41: 187–195.
Hayden MS, Ghosh S . (2004). Genes Dev 18: 2195–2224.
He Q, Huang Y, Sheikh MS . (2004). Oncogene 23: 2554–2558.
Hermisson M, Weller M . (2003). Cell Death Differ 10: 1078–1089.
Hinz M, Loser P, Mathas S, Krappmann D, Dorken B, Scheidereit C . (2001). Blood 97: 2798–2807.
Huang S, DeGuzman A, Bucana CD, Fidler IJ . (2000). Clin Cancer Res 6: 2573–2581.
Jeremias I, Debatin KM . (1998). Eur Cytokine Netw 9: 687–688.
Jiang Y, Cui L, Yie TA, Rom WN, Cheng H, Tchou-Wong KM . (2001). Oncogene 20: 2254–2263.
Johnson TR, Stone K, Nikrad M, Yeh T, Zong WX, Thompson CB et al. (2003). Oncogene 22: 4953–4963.
Karin M, Cao Y, Greten FR, Li ZW . (2002). Nat Rev Cancer 2: 301–310.
Karin M, Yamamoto Y, Wang QM . (2004). Nat Rev Drug Discov 3: 17–26.
Kasperczyk H, La Ferla-Bruhl K, Westhoff MA, Behrend L, Zwacka RM, Debatin KM et al. (2005). Oncogene 24: 6945–6956.
Kasuga C, Ebata T, Kayagaki N, Yagita H, Hishii M, Arai H et al. (2004). Cancer Sci 95: 840–844.
Kim S, Choi K, Kwon D, Benveniste EN, Choi C . (2004). Cell Mol Life Sci 61: 1075–1081.
Lashinger LM, Zhu K, Williams SA, Shrader M, Dinney CP, McConkey DJ . (2005). Cancer Res 65: 4902–4908.
Leverkus M, Sprick MR, Wachter T, Mengling T, Baumann B, Serfling E et al. (2003). Mol Cell Biol 23: 777–790.
Mathas S, Hinz M, Anagnostopoulos I, Krappmann D, Lietz A, Jundt F et al. (2002). EMBO J 21: 4104–4113.
Nagai S, Washiyama K, Kurimoto M, Takaku A, Endo S, Kumanishi T . (2002). J Neurosurg 96: 909–917.
Nencioni A, Wille L, Dal Bello G, Boy D, Cirmena G, Wesselborg S et al. (2005). Clin Cancer Res 11: 4259–4265.
Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C . (1991). J Immunol Methods 139: 271–279.
Nikrad M, Johnson T, Puthalalath H, Coultas L, Adams J, Kraft AS . (2005). Mol Cancer Ther 4: 443–449.
Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM . (2000). Curr Biol 10: 886–895.
Sayers TJ, Brooks AD, Koh CY, Ma W, Seki N, Raziuddin A et al. (2003). Blood 102: 303–310.
Wang CY, Mayo MW, Baldwin Jr AS . (1996). Science 274: 784–787.
Wang H, Zhang W, Huang HJ, Liao WS, Fuller GN . (2004). Lab Invest 84: 941–951.
Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ . (1999). Clin Cancer Res 5: 119–127.
Weaver KD, Yeyeodu S, Cusack Jr JC, Baldwin Jr AS, Ewend MG . (2003). J Neurooncol 61: 187–196.
Yin D, Zhou H, Kumagai T, Liu G, Ong JM, Black KL et al. (2005). Oncogene 24: 344–354.
Zwacka RM, Stark L, Dunlop MG . (2000). J Gene Med 2: 334–343.
Acknowledgements
We thank S Mathas (Max Delbrueck Center for Molecular Medicine, Berlin) for providing KM-H2 cells, Schering-Plough for providing TMZ and S Piater for excellent technical assistance. This work has been partially supported by grants from the Deutsche Forschungsgemeinschaft, Wilhelm-Sander Stiftung and Else-Kröner-Stiftung (to SF and KMD).
Author information
Authors and Affiliations
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
Supplementary information
Rights and permissions
About this article
Cite this article
La Ferla-Brühl, K., Westhoff, M., Karl, S. et al. NF-κB-independent sensitization of glioblastoma cells for TRAIL-induced apoptosis by proteasome inhibition. Oncogene 26, 571–582 (2007). https://doi.org/10.1038/sj.onc.1209841
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1209841
Keywords
This article is cited by
-
PIM kinases mediate resistance of glioblastoma cells to TRAIL by a p62/SQSTM1-dependent mechanism
Cell Death & Disease (2019)
-
Tick-borne encephalitis virus induces chemokine RANTES expression via activation of IRF-3 pathway
Journal of Neuroinflammation (2016)
-
Sensitization of U937 leukemia cells to doxorubicin by the MG132 proteasome inhibitor induces an increase in apoptosis by suppressing NF-kappa B and mitochondrial membrane potential loss
Cancer Cell International (2014)
-
Proteasome inhibitor MG132 induces selective apoptosis in glioblastoma cells through inhibition of PI3K/Akt and NFkappaB pathways, mitochondrial dysfunction, and activation of p38-JNK1/2 signaling
Investigational New Drugs (2012)
-
Inhibition of nuclear factor kappa-B signaling reduces growth in medulloblastoma in vivo
BMC Cancer (2011)