Multi-level disruption of the extrinsic apoptotic pathway mediates resistance of leukemia cells to TNF-related apoptosis-inducing ligand (TRAIL)

Leahomschi, Sergiu; Molinský, Jan; Klánová, Magdalena; Anděra, Ladislav; Peterka, Miroslav; Gašová, Z; Klener, Pavel; Trněný, Marek; Nečas, E; Simonova, Tereza; Živný, J

doi:10.4149/neo_2013_030

Cited by 8 publications

(6 citation statements)

References 43 publications

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“…Tumor necrosis factor-alpha has been reported to be related to a variety of physiological processes, including cytotoxicity and the regulation of anti-viral and immune responses, and most of these processes are regulated through downstream regulatory factors [58,59]. Although TNF-α can destroy tumors, in different environments, it may possess other effects, even acting as an endogenous tumor promoter [27-29,60].…”

Section: Discussionmentioning

confidence: 99%

NF-κB-modulated miR-130a targets TNF-α in cervical cancer cells

Zhang

et al. 2014

J Transl Med

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BackgroundNuclear factor-κB (NF-κB) induces a variety of biological processes through transcriptional gene control whose products are components in various signaling pathways. MicroRNAs are a small endogenous non-coding RNAs that regulate gene expression and are involved in tumorigenesis. Using human cervical cancer cell lines, this study aimed to investigate whether NF-κB could regulate miR-130a expression and the functions and targets of miR-130a.MethodsWe used the HeLa and C33A cervical cancer cell lines that were transfected with NF-κB or miR-130a overexpression plasmids to evaluate their effects on cell growth. We utilized bioinformatics, a fluorescent reporter assay, qRT-PCR and Western blotting to identify downstream target genes.ResultsIn HeLa and C33A cells, NF-κB and miR-130a overexpression promoted cell growth, but genetic knockdowns suppressed growth. TNF-α was identified as a target of miR-130a by binding in a 3’-untranslated region (3’UTR) EGFP reporter assay and by Western blot analysis. Furthermore, low TNF-α concentrations stimulated NF-κB activity and then induced miR-130a expression, and TNF-α overexpression rescued the effects of miR-130a on cervical cancer cells.ConclusionsOur findings indicate that TNF-α can activate NF-κB activity, which can reduce miR-130a expression, and that miR-130a targets and downregulates TNF-α expression. Hence, we shed light on the negative feedback regulation of NF-κB/miR-130a/TNF-α/NF-κB in cervical cancer and may provide insight into the carcinogenesis of cervical cancer.

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Section: Discussionmentioning

confidence: 99%

NF-κB-modulated miR-130a targets TNF-α in cervical cancer cells

Zhang

et al. 2014

J Transl Med

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“…In addition, beneficial alterations in the ratios of pro-apoptotic proteins, Bax and Bak, protein expressions and the anti-apoptotic proteins, Bcl-xL, Mcl-1 and cFLIP, favors overcoming the resistance to TRAIL. 45, 46 Finally, elevations in all three isoforms of Bim contribute to a higher apoptotic response. 47, 48 …”

Section: Discussionmentioning

confidence: 99%

Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways

et al. 2014

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Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAFV600E have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner by activating the extrinsic apoptotic pathway. Here, we show that a TRAIL-R2 agonist antibody, lexatumumab, induces apoptosis effectively in some thyroid cancer cell lines (HTh-7, TPC-1 and BCPAP), while more aggressive anaplastic cell lines (8505c and SW1736) show resistance. Treatment of the most resistant cell line, 8505c, using lexatumumab in combination with the BRAFV600E inhibitor, PLX4720, and the PI3K inhibitor, LY294002, (triple-drug combination) sensitizes the cells by triggering both the extrinsic and intrinsic apoptotic pathways in vitro as well as 8505c orthotopic thyroid tumors in vivo. A decrease in anti-apoptotic proteins, pAkt, Bcl-xL, Mcl-1 and c-FLIP, coupled with an increase in the activator proteins, Bax and Bim, results in an increase in the Bax to Bcl-xL ratio that appears to be critical for sensitization and subsequent apoptosis of these resistant cells. Our results suggest that targeting the death receptor pathway in thyroid cancer can be a promising strategy for inducing apoptosis in thyroid cancer cells, although combination with other kinase inhibitors may be needed in some of the more aggressive tumors initially resistant to apoptosis.

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“…Resistance to TRAIL is partially explained by decoy receptors (DcR1 and DcR2), which have a deleted or truncated death domain [ 6 ]. Other defects of cell death pathways, such as dysregulated expression of anti-apoptotic proteins and pro-apoptotic proteins, were identified as mechanisms of resistance [ 4 , 7 ]. However, new biomarkers and molecular targets of TRAIL resistance are still needed for its potential future clinical use.…”

Section: Introductionmentioning

confidence: 99%

Bay 61-3606 Sensitizes TRAIL-Induced Apoptosis by Downregulating Mcl-1 in Breast Cancer Cells

et al. 2015

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Breast cancer cells generally develop resistance to TNF-Related Apoptosis-Inducing Ligand (TRAIL) and, therefore, assistance from sensitizers is required. In our study, we have demonstrated that Spleen tyrosine kinase (Syk) inhibitor Bay 61–3606 was identified as a TRAIL sensitizer. Amplification of TRAIL-induced apoptosis by Bay 61–3606 was accompanied by the strong activation of Bak, caspases, and DNA fragmentation. In mechanism of action, Bay 61–3606 sensitized cells to TRAIL via two mechanisms regulating myeloid cell leukemia sequence-1 (Mcl-1). First, Bay 61–3606 triggered ubiquitin-dependent degradation of Mcl-1 by regulating Mcl-1 phosphorylation. Second, Bay 61–3606 downregulates Mcl-1 expression at the transcription level. In this context, Bay 61–3606 acted as an inhibitor of Cyclin-Dependent Kinase (CDK) 9 rather than Syk. In summary, Bay 61–3606 downregulates Mcl-1 expression in breast cancer cells and sensitizes cancer cells to TRAIL-mediated apoptosis.

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Multi-level disruption of the extrinsic apoptotic pathway mediates resistance of leukemia cells to TNF-related apoptosis-inducing ligand (TRAIL)

Cited by 8 publications

References 43 publications

NF-κB-modulated miR-130a targets TNF-α in cervical cancer cells

NF-κB-modulated miR-130a targets TNF-α in cervical cancer cells

Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways

Bay 61-3606 Sensitizes TRAIL-Induced Apoptosis by Downregulating Mcl-1 in Breast Cancer Cells

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