NF-κB-dependent MnSOD expression protects adenocarcinoma cells from TNF-α-induced apoptosis

Delhalle, Sylvie; Deregowski, Valérie; Benoît, Valérie; Merville, Marie‐Paule; Bours, Vincent

doi:10.1038/sj.onc.1205489

Cited by 108 publications

(85 citation statements)

References 53 publications

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“…NEMO-ATM complexes are then able to exit the nucleus and trigger IKK activation in the cytoplasm (20,23), resulting in IB␣ phosphorylation and proteasomal degradation (77). This leads in turn to the release and nuclear translocation of p65/ RelA and transcriptional activation of multiple NF-B-dependent genes, including the ROS scavenger Mn-SOD2 (78,79), which eliminates ROS and limits further DNA damage and cell death. Such a model may have implications for attempts to enhance the antileukemic activity of HDACIs.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

Rosato

Kolla

Hock

et al. 2010

Journal of Biological Chemistry

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In accord with the recently described DNA damage/ATM/NEMO pathway, SUMOylation site mutant NEMO (K277A or K309A) cells exposed to LBH-589 displayed diminished ATM/NEMO association, NEMO and p65/RelA nuclear localization/activation, and MnSOD2 up-regulation. These events were accompanied by increased ROS production, ␥-H2AX formation, and cell death. Together, these findings indicate that in human leukemia cells, HDACIs activate the cytoprotective NF-B pathway through an ATM/NEMO/SUMOylation-dependent process involving the induction of ROS and DNA damage and suggest that blocking NF-B activation via the atypical ATM/NEMO nuclear pathway can enhance HDACI antileukemic activity.Chromatin structure and gene expression are regulated by reversible acetylation of lysine residues in histone tails, a process comprising a component of the histone code (1). Histone acetylation is regulated reciprocally by histone deacetylases (HDACs) 2 and histone acetylase transferases (2). Histone deacetylase inhibitors, a group of structurally diverse compounds, have shown encouraging activity in certain hematopoietic malignancies, including cutaneous T-cell lymphoma and acute leukemia (3,4). Numerous mechanisms have been proposed to account for HDACI-mediated lethality, including oxidative damage, up-regulation of death receptors or proapoptotic proteins (e.g. Bim), down-regulation of anti-apoptotic proteins, and more recently, DNA damage induction and/or interference with DNA repair proteins (3,5,6).HDACIs also increase acetylation of various non-histone proteins including chaperone proteins (7), DNA repair proteins (e.g. Ku70) (8), and transcription factors, e.g. YY-1, E2F, and NF-B (9, 10). Of the latter, NF-B is a particularly important determinant of HDACI actions, particularly proliferation, differentiation, and cell death (11-13). NF-B consists of a family of proteins including p65/RelA, RelB, c-Rel, p105, p100, p52, and p50, which form homo-and heterodimers, of which p65/ p50 is the most abundant (14). Various cytokines (e.g. TNF␣, interleukin-1, and lipopolysaccharides) and environmental stresses trigger the classical NF-B pathway by activating the IKK complex, which consists of IKK␣, IKK␤, and IKK␥/NEMO (NF-B-essential modulator) (15). This leads to phosphorylation (Ser-32/Ser-36), ubiquitination, and proteasomal degradation of IB␣, resulting in p65 nuclear translocation, DNA binding, and activation of prosurvival genes, including . Other stimuli (e.g. CD-40 ligation, lymphotoxin-␤, and B-cell-activating factor (BAFF)) activate the alternative (noncanonical) NF-B pathway through a complex consisting of NF-B-inducing kinase (NIK) and IKK␣ but not IKK␤ (16). A third, atypical, UV light-associated pathway activates p65 via p38 mitogen-activated protein kinase (MAPK) and CSII * This work was supported, in whole or in part, by National Institutes of Health Grants CA63753, CA93738, and CA100866 from the National Cancer Institute, the Leukemia and Lymphoma Society of America, and Lymphoma SPORE Award 1P50 CA130805. This work was al...

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Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

Rosato

Kolla

Hock

et al. 2010

Journal of Biological Chemistry

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“…It was implicated in NF-kB-mediated suppression of JNK in response to TNF, and in mediating the cytoprotective activity of CD40 against Fas-induced death in B cells (De Smaele et al, 2001;Zazzeroni et al, 2003a). MnSOD also belongs to this category, as an NF-kBinduced enzyme that scavenges cytotoxic ROS generated by various apoptotic pathways (Bernard et al, 2001a(Bernard et al, , 2002Delhalle et al, 2002;Tanaka et al, 2002). Lastly, there have been new developments regarding the controversial role of the immediate-early response gene iex-1 in NF-kB-mediated survival.…”

Section: Mechanisms For Nf-kb-mediated Protection From Apoptosismentioning

confidence: 99%

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

et al. 2003

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“…Western blot analysis showed no differences in expression of the apoptosis inhibitors FAP-1, FLIP, Bcl-2, Bcl-X L and XIAP between the cell lines. The nonspecific anti-XIAP and Bc1-X L , immunoreactive molecule as indicated (*) served as an internal loading control (Deveraux et al, 1999, Delhalle et al, 2002 (Figure 2B). There were also no differences in COX-2 expression ( Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

Indomethacin-induced activation of the death receptor-mediated apoptosis pathway circumvents acquired doxorubicin resistance in SCLC cells

et al. 2005

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Small-cell lung cancers (SCLCs) initially respond to chemotherapy but are often resistant at recurrence. A potentially new method to overcome resistance is to combine classical chemotherapeutic drugs with apoptosis induction via tumour necrosis factor (TNF) death receptor family members such as Fas. The doxorubicin-resistant human SCLC cell line GLC 4 -Adr and its parental doxorubicinsensitive line GLC 4 were used to analyse the potential of the Fas-mediated apoptotic pathway and the mitochondrial apoptotic pathway to modulate doxorubicin resistance in SCLC. Western blotting showed that all proteins necessary for death-inducing signalling complex formation and several inhibitors of apoptosis were expressed in both lines. The proapototic proteins Bid and caspase-8, however, were higher expressed in GLC 4 -Adr. In addition, GLC 4 -Adr expressed more Fas (3.1x) at the cell membrane. Both lines were resistant to anti-Fas antibody, but plus the protein synthesis inhibitor cycloheximide anti-Fas antibody induced 40% apoptosis in GLC 4 -Adr. Indomethacin, which targets the mitochondrial apoptotic pathway, induced apoptosis in GLC 4 -Adr but not in GLC 4 cells. Surprisingly, in GLC 4 -Adr indomethacin induced caspase-8 and caspase-9 activation as well as Bid cleavage, while both caspase-8 and caspase-9 specific inhibitors blocked indomethacin-induced apoptosis. In GLC 4 -Adr, doxorubicin plus indomethacin resulted in elevated caspase activity and a 2.7-fold enhanced sensitivity to doxorubicin. In contrast, no effect of indomethacin on doxorubicin sensitivity was observed in GLC 4 . Our findings show that indomethacin increases the cytotoxic activity of doxorubicin in a doxorubicin-resistant SCLC cell line partly via the death receptor apoptosis pathway, independent of Fas.

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NF-κB-dependent MnSOD expression protects adenocarcinoma cells from TNF-α-induced apoptosis

Cited by 108 publications

References 53 publications

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

Histone Deacetylase Inhibitors Activate NF-κB in Human Leukemia Cells through an ATM/NEMO-related Pathway

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

Indomethacin-induced activation of the death receptor-mediated apoptosis pathway circumvents acquired doxorubicin resistance in SCLC cells

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