NF-κB-independent sensitization of glioblastoma cells for TRAIL-induced apoptosis by proteasome inhibition

Ferla-Brühl, Katia La; Westhoff, Mike‐Andrew; Karl, Sabine; Kasperczyk, Hubert; Zwacka, Ralf M.; Debatin, Klaus‐Michael; Fulda, Simone

doi:10.1038/sj.onc.1209841

Cited by 38 publications

(31 citation statements)

References 37 publications

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“…In some studies, NF-B inhibition by proteasome inhibitors was insufficient to explain the observed synergy between proteasome inhibitors and TRAIL such as in glioblastoma (19) or the chemoresistant Bcl-2-overexpressing cells, where most likely Bcl-2 cleavage and elimination of antiapoptotic Mcl-1 may both play a role in the proteasome inhibitor-TRAIL cooperation (22). Similarly, novel NF-B and death receptor-independent mechanisms have been proposed in reversal of primary keratinocyte resistance to TRAIL by proteasome inhibitors including removal of the downstream resistance-mediating block of effector caspase maturation (37).…”

Section: Discussionmentioning

confidence: 99%

“…There are several reports indicating a synergistic apoptotic response achieved by the combination of TRAIL with chemotherapeutic drugs (13,14). Increased apoptotic rates in a variety of cancer cell lines have also been reported after the combination of TRAIL with proteasome inhibitors resulting by augmentation of DR5 protein levels (15)(16)(17)(18)(19)(20)(21)(22)(23). Although the role of DR5 up-regulation and involvement in TRAIL-induced sensitization to apoptosis by proteasome inhibitors is well documented, the mechanism by which DR5 is up-regulated is not known and is the subject of the present investigation.…”

Section: Inhibition Of Yin Yang 1-dependent Repressor Activity Of Dr5mentioning

confidence: 99%

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Inhibition of Yin Yang 1-Dependent Repressor Activity of DR5 Transcription and Expression by the Novel Proteasome Inhibitor NPI-0052 Contributes to its TRAIL-Enhanced Apoptosis in Cancer Cells

Baritaki

Suzuki

Umezawa

et al. 2008

The Journal of Immunology

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TRAIL promotes apoptotic tumor cell death; however, TRAIL-resistant tumors need to be sensitized to reverse resistance. Proteasome inhibitors potentiate TRAIL apoptosis in vitro and in vivo and correlate with up-regulation of death receptor 5 (DR5) via an unknown mechanism. We hypothesized that the proteasome inhibitor NPI-0052 inhibits the transcription repressor Yin Yang 1 (YY1) which regulates TRAIL resistance and negatively regulates DR5 transcription. Treatment of PC-3 and Ramos cells with NPI-0052 (≤2.5 nM) and TRAIL sensitizes the tumor cells to TRAIL-induced apoptosis. By comparison to bortezomib, a 400-fold less concentration of NPI-0052 was used. NPI-0052 up-regulated DR5 reporter activity and both surface and total DR5 protein expression. NPI-0052-induced inhibition of NF-κB activity was involved in TRAIL sensitization as corroborated by the use of the NF-κB inhibitor dehydroxymethylepoxyquinomicin. NPI-0052 inhibited YY1 promoter activity as well as both YY1 mRNA and protein expression. The direct role of NPI-0052-induced inhibition of YY1 and up-regulation of DR5 in the regulation of TRAIL sensitivity was demonstrated by the use of YY1 small interfering RNA. The NPI-0052-induced sensitization to TRAIL involved activation of the intrinsic apoptotic pathway and dysregulation of genes that regulate apoptosis. The NPI-0052 concentrations used for TRAIL sensitization were not toxic to human hematopoetic stem cells. The present findings demonstrate, for the first time, the potential mechanism by which a proteasome inhibitor, like NPI-0052, inhibits the transcription repressor YY1 involved in TRAIL resistance and DR5 regulation. The findings also suggest the therapeutic application of subtoxic NPI-0052 concentrations in combination with TRAIL/agonist DR4/DR5 mAbs in the treatment of TRAIL-resistant tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Inhibition Of Yin Yang 1-dependent Repressor Activity Of Dr5mentioning

confidence: 99%

Inhibition of Yin Yang 1-Dependent Repressor Activity of DR5 Transcription and Expression by the Novel Proteasome Inhibitor NPI-0052 Contributes to its TRAIL-Enhanced Apoptosis in Cancer Cells

Baritaki

Suzuki

Umezawa

et al. 2008

The Journal of Immunology

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“…It is known that pIκb· regulates NF-κB nuclear transport. 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 (23). By retarding the nuclear transport of NF-κB, survival molecules may be underexpressed and may trigger mitochondrial or caspase-mediated apoptosis as seen in our experiments.…”

Section: Discussionmentioning

confidence: 65%

RNAi-mediated downregulation of MMP-2 activates the extrinsic apoptotic pathway in human glioma xenograft cells

Gondi

Talluri

Dinh³

et al. 2009

Int J Oncol

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Abstract. Malignant gliomas are characterized by invasive and infiltrative behavior that generally involves the destruction of normal brain tissue. Strategies to treat infiltrating gliomas, such as chemotherapy and gene therapy, have remained largely unsuccessful. The infiltrative nature of gliomas can be attributed largely to proteases, which include serine, metallo-and cysteine-proteases. Our previous work and that of others strongly suggest a relationship between the expression of uPAR, MMP-9, and MMP-2; this relationship is generally indicative of the infiltrative phenotype of gliomas. In the present study, we have demonstrated that the RNAi-mediated downregulation of MMP-2 induces apoptosis in the 4910 human glioma xenograft cell line. Using Western blot analysis, we observed that caspase-8 levels increased in MMP-2-downregulated cells whereas TRADD and TRAF-2 levels decreased. Further, NIK levels increased in MMP-2-downregulated cells. To determine the nuclear localization of AIF and IκB·, we analyzed the levels of AIF, IκB· and pIκB· in the cytosolic and nuclear fractions of MMP-2-downregulated cells. Western blot analysis revealed that MMP-2 downregulation resulted in the translocation of AIF to the nucleus and also inhibited the nuclear localization of pIκB·. To confirm the involvement of AIF, we performed FACS analysis to determine the integrity of the mitochondrial membrane using the MitoPT method. FACS analysis showed that the downregulation of MMP-2 caused a collapse in the mitochondrial cell membrane. Immunolocalization of AIF revealed that in MMP-2-downregulated cells, AIF translocates to the nucleus, thereby enabling the induction of apoptosis. RT-PCR analysis revealed that caspase-8 was overexpressed 57-fold, whereas p73 was downregulated 28-fold. Evidence of apoptosis was determined by TUNEL assay and visualization of nuclear fragmentation by DAPI staining. In summary, it is evident from our results that MMP-2 downregulation induces caspase-8 and AIF-mediated apoptosis and, as such, shows potential for glioma therapy.

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“…Several mechanisms by which curcumin exerts its anticancer effect have been reported, in the first line by inhibition of NF-kB (20). However, GBM cells were found to have little or no active NF-kB (42), and when in curcumin-treated GBM cells NF-kB p65 was knocked down, the viability of these cells did not change suggesting that the anticancer effect of curcumin seen in these cells was not caused by inhibition of NF-kB (7).…”

Section: Discussionmentioning

confidence: 99%

Dietary Curcumin Attenuates Glioma Growth in a Syngeneic Mouse Model by Inhibition of the JAK1,2/STAT3 Signaling Pathway

Weissenberger

Priester

Bernreuther

et al. 2010

Clinical Cancer Research

123

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Purpose: Glioblastomas are the most common and most deadly primary brain tumors. Here, we evaluated the chemotherapeutic effect of the natural polyphenol curcumin on glioma cells in vitro and in vivo using an immunocompetent orthotopic mouse model.Experimental Design: Curcumin's effects on proliferation, cell cycle, migration, invasion, JAK/STAT3 signaling, STAT3 target gene expression, and STAT3C rescue experiments were determined in murine glioma cell lines in vitro. Therapeutic effects of curcumin in vivo were evaluated in tumor-bearing mice fed a Western-type diet fortified with curcumin (0.05%, w/w) and in control animals. Tumor growth patterns and survival were evaluated by immunohistochemistry, morphometric analyses, and Kaplan-Meier plots.Results: In vitro, curcumin inhibited JAK1,2/STAT3 tyrosine-phosphorylation in a dose-dependent fashion in murine glioma cell lines. Real-time RT-PCR revealed that curcumin downregulated transcription of the STAT3 target genes c-Myc, MMP-9, Snail, and Twist, and of the proliferation marker Ki67. Curcumin dose-dependently suppressed cell proliferation by inducing a G2/M phase arrest. In wound healing and Matrigel invasion assays, curcumin treatment resulted in a dose-dependent attenuation of the glioma cells' migratory and invasive behavior, which could be rescued by constitutively active STAT3C. In vivo, curcumin intake reduced the growth and midline crossing of intracranially implanted tumors and proliferation of tumor cells ensuing in significant long-term survival compared with control diet.Conclusion: This preclinical study shows that curcumin is capable of suppressing malignant glioma growth in vitro and in vivo. Our data suggest that the pharmacologically safe agent curcumin holds promise for clinical application in glioma therapy. Clin Cancer Res; 16(23); 5781-95. Ó2010 AACR.

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NF-κB-independent sensitization of glioblastoma cells for TRAIL-induced apoptosis by proteasome inhibition

Cited by 38 publications

References 37 publications

Inhibition of Yin Yang 1-Dependent Repressor Activity of DR5 Transcription and Expression by the Novel Proteasome Inhibitor NPI-0052 Contributes to its TRAIL-Enhanced Apoptosis in Cancer Cells

Inhibition of Yin Yang 1-Dependent Repressor Activity of DR5 Transcription and Expression by the Novel Proteasome Inhibitor NPI-0052 Contributes to its TRAIL-Enhanced Apoptosis in Cancer Cells

RNAi-mediated downregulation of MMP-2 activates the extrinsic apoptotic pathway in human glioma xenograft cells

Dietary Curcumin Attenuates Glioma Growth in a Syngeneic Mouse Model by Inhibition of the JAK1,2/STAT3 Signaling Pathway

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