Abstract
Resistance of glioblastoma multiforme (GBM) to TNFα induced apoptosis is attributed to NFκB activation. As TNF-receptor family member CD40 regulates NFκB activation, we investigated the role of CD40 in NFκB activation in GBM. We observed elevated CD40 levels in human glioma samples as compared to the surrounding normal tissue. Treatment with TNFα elevated CD40 levels in glioma cells and inhibition of CD40 signaling failed to abrogate TNFα induced NFκΒ activity. While TNFα increased the interaction between TRAF2/6, IκBα, IKKα/β in the CD40 signalosome, the level of CD40 in the signalosome remained unaffected upon TNFα treatment. Interestingly, TNFα decreased the spatial localization of CD40 and increased TRAF2/6 co-localization with lipid raft marker Caveolin. As localization of CD40 signalosome in lipid raft is crucial for NFκB activation, TNFα mediated decreased clustering of CD40 in lipid rafts could have possibly contributed to its non-involvement in NFκB activation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Tsujimoto M, Yip YK, Vilcek J (1985) Tumor necrosis factor: specific binding and internalization in sensitive and resistant cells. Proc Natl Acad Sci USA 82(22):7626–7630
Beg AA, Baltimore D (1996) An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274(5288):782–784
Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM (1996) Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 274(5288):787–789
Wang CY, Mayo MW, Baldwin AS Jr (1996) TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 274(5288):784–787
Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr (1998) NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281(5383):1680–1683
Tewari R, Choudhury SR, Ghosh S, Mehta VS, Sen E (2012) Involvement of TNFalpha-induced TLR4-NF-kappaB and TLR4-HIF-1alpha feed-forward loops in the regulation of inflammatory responses in glioma. J Mol Med 90(1):67–80
Sharma V, Tewari R, Sk UH, Joseph C, Sen E (2008) Ebselen sensitizes glioblastoma cells to Tumor Necrosis Factor (TNFalpha)-induced apoptosis through two distinct pathways involving NF-kappaB downregulation and Fas-mediated formation of death inducing signaling complex. Int J Cancer 123(9):2204–2212
Dixit D, Sharma V, Ghosh S, Mehta VS, Sen E Inhibition of Casein kinase-2 induces p53-dependent cell cycle arrest and sensitizes glioblastoma cells to tumor necrosis factor (TNFalpha)-induced apoptosis through SIRT1 inhibition. Cell Death Dis 3(2):e271
Pham LV, Tamayo AT, Yoshimura LC, Lo P, Terry N, Reid PS et al (2002) A CD40 Signalosome anchored in lipid rafts leads to constitutive activation of NF-kappaB and autonomous cell growth in B cell lymphomas. Immunity 16(1):37–50
Zhou Y, He J, Gou LT, Mu B, Liao WC, Ma C et al Expression of CD40 and growth-inhibitory activity of CD40 agonist in ovarian carcinoma cells. Cancer Immunol Immunother Mar 11 [Epub ahead of print]
Posner MR, Cavacini LA, Upton MP, Tillman KC, Gornstein ER, Norris CM Jr (1999) Surface membrane-expressed CD40 is present on tumor cells from squamous cell cancer of the head and neck in vitro and in vivo and regulates cell growth in tumor cell lines. Clin Cancer Res 5(8):2261–2270
Wischhusen J, Schneider D, Mittelbronn M, Meyermann R, Engelmann H, Jung G et al (2005) Death receptor-mediated apoptosis in human malignant glioma cells: modulation by the CD40/CD40L system. J Neuroimmunol 162(1–2):28–42
Xie F, Shi Q, Wang Q, Ge Y, Chen Y, Zuo J et al (2010) CD40 is a regulator for vascular endothelial growth factor in the tumor microenvironment of glioma. J Neuroimmunol 222(1–2):62–69
Tewari R, Sharma V, Koul N, Sen E (2008) Involvement of Miltefosine mediated ERK activation in glioma cell apoptosis through Fas regulation. J Neurochem 107(3):616–627
Sen E (2011) Targeting inflammation-induced transcription factor activation: an open frontier for glioma therapy. Drug Discov Today 16(23–24):1044–1051
Sharma V, Koul N, Joseph C, Dixit D, Ghosh S, Sen E (2009) HDAC inhibitor Scriptaid induces glioma cell apoptosis through JNK activation and inhibits telomerase activity. J Cell Mol Med 14(8):2151–2161
Sharma V, Dixit D, Koul N, Mehta VS, Sen E (2011) Ras regulates interleukin-1beta-induced HIF-1alpha transcriptional activity in glioblastoma. J Mol Med (Berl) 89(2):123–136
Sun H, Zhong YJ, Zheng XL, Wang Q, Yang L, Shi F et al (2012) Critical role of CD40-mediated autocrine tumor necrosis factor-alpha in potentiation of cisplatin-induced cytotoxicity in cancer cells. Cancer Sci 103(2):197–202
Mehl AM, Jones M, Rowe M, Brennan P (2001) Characterization of a CD40-dominant inhibitory receptor mutant. J Immunol 167(11):6388–6393
Acknowledgments
This work was supported by the Innovative Young Biotechnologist Award (IYBA) research grant from the Department of Biotechnology, Government of India, to ES.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Tewari, R., Choudhury, S.R., Mehta, V.S. et al. TNFα regulates the localization of CD40 in lipid rafts of glioma cells. Mol Biol Rep 39, 8695–8699 (2012). https://doi.org/10.1007/s11033-012-1726-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-012-1726-5