Butyrate sensitizes human colon cancer cells to TRAIL-mediated apoptosis

Hernandez, Ambrosio; Thomas, Robert Paul; Smith, Farin; Sandberg, Jennie; Kim, Sung‐Hoon; Chung, Dai H.; Evers, B. Mark

doi:10.1067/msy.2001.115897

Cited by 69 publications

(49 citation statements)

References 21 publications

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“…Sodium butyrate has been proposed to disrupt the association of HDAC with Sp1, which in turn may lead to the decondensation of local chromatin, activate the transcription of DR5, and activate TRAILinduced apoptotic signaling pathways in colon cancer cells (Kim et al, 2004a). Decreased expression of FLIP, which functions as a dominant negative inhibitor of caspase-8 due to its structural resemblance to caspase-8 without proteolytic activity, has also been proposed to be involved in this sensitizing effect of sodium butyrate (Hernandez et al, 2001). In our study, combined treatment with sodium butyrate and TRAIL, but not either agent alone, significantly induced apoptosis in various glioma cell lines.…”

Section: Discussionmentioning

confidence: 60%

“…However, basal DR5 protein levels were fairly high in both U87MG cells and A172 cells, and DR5 upregulation following exposure to sodium butyrate was not dramatic. Recently, reduction in the protein levels of the caspase inhibitor FLIP by sodium butyrate has been implicated in the sensitization of colon cancer cells and Jurkat cells to TRAIL-induced apoptosis (Hernandez et al, 2001;Guo et al, 2004). However, FLIP protein levels were not changed following sodium butyrate treatment in either U87MG or A172 cells (Figure 5a).…”

Section: Sodium Butyrate Sensitizes Trail-induced Apoptosis In Gliomamentioning

confidence: 79%

“…However, the underlying mechanisms by which HDAC inhibitors sensitize cancer cells to TRAIL-induced apoptosis are still poorly understood. Recently, upregulation of DR5, a death receptor of TRAIL (Guo et al, 2004;Kim et al, 2004a;Nakata et al, 2004), downregulation of FLIP (Hernandez et al, 2001;Guo et al, 2004), or p21 induction (Chopin et al, 2004) has been proposed as the potential mechanisms through which HDAC inhibitors enhance TRAIL-induced apoptosis. In this study, we show that combined treatment with subtoxic doses of sodium butyrate and TRAIL dramatically induces apoptosis in TRAILresistant glioma cells.…”

Section: Introductionmentioning

confidence: 99%

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Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP

Kim

et al. 2005

Oncogene

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In TNF-related apoptosis-inducing ligand (TRAIL)-resistant glioma cells, co-treatment with nontoxic doses of sodium butyrate and TRAIL resulted in a marked increase of TRAIL-induced apoptosis. This combined treatment was also cytotoxic to glioma cells overexpressing Bcl-2 or Bcl-xL, but not to normal human astrocytes, thus offering an attractive strategy for safely treating resistant gliomas. Cotreatment with sodium butyrate facilitated completion of proteolytic processing of procaspase-3 that was partially blocked by treatment with TRAIL alone. We also found that treatment with sodium butyrate significantly decreased the protein levels of survivin and X-linked inhibitor of apoptosis protein (XIAP), two major caspase inhibitors. Overexpression of survivin and XIAP attenuated sodium butyratestimulated TRAIL-induced apoptosis, suggesting its involvement in conferring TRAIL resistance to glioma cells. Furthermore, the kinase activities of Cdc2 and Cdk2 were significantly decreased following sodium butyrate treatment, accompanying downregulation of cyclin A and cyclin B, as well as upregulation of p21. Forced expression of Cdc2 plus cyclin B, but not Cdk2 plus cyclin A, attenuated sodium butyrate/TRAIL-induced apoptosis, overriding sodium butyrate-mediated downregulation of survivin and XIAP. Therefore, Cdc2-mediated downregulation of survivin and XIAP by sodium butyrate may contribute to the recovery of TRAIL sensitivity in glioma cells.

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Section: Discussionmentioning

confidence: 60%

Section: Sodium Butyrate Sensitizes Trail-induced Apoptosis In Gliomamentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP

Kim

et al. 2005

Oncogene

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“…c-FLIP structurally resembles caspase-8 but lacks proteolytic activity, and it blocks death receptor-mediated signaling by preventing caspase 8 activation at the DISC formed by DR4 and/or DR5 stimulation [8]. Many previous reports have shown that HDACIs enhance TRAIL-induced apoptosis by downregulating c-FLIP in various tumor types, such as by sodium butyrate in human colon carcinoma cells [40], by VPA in primary CLL cells isolated from patients [17] and by LAQ824 in Jurkat and HL-60 ALL cells [37]. In both CCRF-CEM and CEM-CM3 cells, compared with the single agent treatments, the combination of AY4 or TRAIL with SAHA or VPA triggered much faster and more substantial decreases in c-FLIP L expression, which in turn increased caspase-8 activation and Bid cleavage to subsequently activate both the extrinsic and intrinsic apoptotic pathways.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

et al. 2010

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Cell-death signaling through the pro-apoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, death receptor 4 (DR4) and DR5, has shown tumor-selective apoptotic activity. Here, we examine susceptibility of various leukemia cell lines (HL-60, U937, K562, CCRF-CEM, CEM-CM3, and THP-1) to an anti-DR4 agonistic monoclonal antibody (mAb), AY4, in comparison with TRAIL. While most of the leukemia cell lines were intrinsically resistant to AY4 or TRAIL alone, the two T-cell acute lymphoblastic leukemia (T-ALL) lines, CEM-CM3 and CCRF-CEM cells, underwent synergistic caspase-dependent apoptotic cell death by combination of AY4 or TRAIL with a histone deacetylase inhibitor (HDACI), either suberoylanilide hydroxamic acid (SAHA) or valproic acid (VPA). All of the combined treatments synergistically downregulated several antiapoptotic proteins (c-FLIP, Bcl-2, Bcl-X L , XIAP, and survivin) without significant changing the expression levels of pro-apoptotic proteins (Bax and Bak) or the receptors (DR4 and DR5). Downregulation of c-FLIP to activate caspase-8 was a critical step for the synergistic apoptosis through both extrinsic and intrinsic apoptotic pathways. Our results demonstrate that the HDACIs have synergistic effects on DR4-specific mAb AY4-mediated cell death in the T-ALL cells with comparable competence to those exerted by TRAIL, providing a new strategy for the targeted treatment of human T-ALL cells.

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“…Together, these findings indicate that TRAIL/FP-induced apoptosis is associated with markedly enhanced caspase activation, cytosolic depletion of Bax, and mitochondrial damage. On the other hand, and in view of evidence that TRAIL, either alone or in combination, may induce cell death by altering expression of death receptors or FLIP (FLICE-like inhibitory protein), 26 expression of these proteins was monitored in TRAIL/FP-treated U937 cells. No changes were observed in the levels of DR4, DR5, or FLIP, although a slight decline in expression of the decoy receptor DcR2 was noted (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation

et al. 2004

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Interactions between the cyclin-dependent kinase inhibitor flavopiridol (FP) and tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL/Apo2L), were examined in human leukemia cells (U937 and Jurkat). Coexposure of cells to marginally toxic concentrations of TRAIL and FP (24 h) synergistically increased mitochondrial injury (eg, cytochrome c, AIF, Smac/DIABLO release), cytoplasmic depletion of Bax, activation of Bid as well as caspase-8 and -3, PARP cleavage, and apoptosis. Coadministration of TRAIL markedly increased FP-induced apoptosis in leukemic cells ectopically expressing Bcl-2, Bcl-x L , or a phosphorylation loop-deleted form of Bcl-2 (DBcl-2), whereas lethality was substantially attenuated in cells ectopically expressing CrmA, dominant-negative-FADD, or dominant-negative-caspase-8. TRAIL/ FP induced no discernible changes in FLIP, DR4, DR5, Mcl-1, or survivin expression, modest declines in levels of DcR2 and c-IAP, but resulted in the marked transcriptional downregulation of XIAP. Moreover, cells stably expressing an XIAP-antisense construct exhibited a pronounced increase in TRAIL sensitivity comparable to degrees of apoptosis achieved with TRAIL/FP. Conversely, enforced XIAP expression significantly attenuated caspase activation and TRAIL/FP lethality. Together, these findings suggest that simultaneous activation of the intrinsic and extrinsic apoptotic pathways by TRAIL and FP synergistically induces apoptosis in human leukemia cells through a mechanism that involves FPmediated XIAP downregulation.

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Butyrate sensitizes human colon cancer cells to TRAIL-mediated apoptosis

Cited by 69 publications

References 21 publications

Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP

Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP

Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

Potent antileukemic interactions between flavopiridol and TRAIL/Apo2L involve flavopiridol-mediated XIAP downregulation

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