Loss of expression of death-inducing signaling complex (DISC) components in lung cancer cell lines and the influence of MYC amplification

Shivapurkar, Narayan; Reddy, Jyotsna; Matta, Hittu; Sathyanarayana, Ubaradka G.; Huang, Chun Xian; Toyooka, Shinichi; Minna, John D.; Chaudhary, Preet M.; Gazdar, Adi F.

doi:10.1038/sj.onc.1205941

Cited by 67 publications

(46 citation statements)

References 24 publications

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“…Aberrant methylation of DR4 and DR5 was observed only in a few cell lines. Based on our previous findings of loss of expression data for DR4 (non-small cell lung cancer, 10%; small cell lung cancer, 20%) and DR5 (non-small cell lung cancer, 35%; small cell lung cancer, 50%) in lung cancer cell lines 19 there was no significant concordance between methylation and loss of gene expression.…”

Section: Aberrant Methylation In Cell Linesmentioning

confidence: 84%

“…We focused on 5 lung cancer cell lines reported in our previous publication 19 that were positive for expression of all DISC components but positive or negative for the expression of decoy receptors (NCI-H460, NCI-H1339 negative for both DcR1 and DcR2; NCI-H1703, NCI-H2195 positive for DcR1 but negative for DcR2 whereas NCI-H2347 positive for both DcR1 and DcR2). Cells were cultured in RPMI medium supplemented with 5% FBS at 37°C with 5% CO 2 .…”

Section: Trail Sensitivity Assaymentioning

confidence: 99%

“…Cell survival was quantitated using MTS assay. 19 Sensitivity to TRAIL was measured as percentage survival compared to the untreated controls.…”

Section: Trail Sensitivity Assaymentioning

confidence: 99%

“…9 -18 We have demonstrated loss of expression (at RNA and protein level) of DR4 and DR5 in lung cancer cell lines, although the mechanism was not via methylation. 19 Recently, 20 it was reported that DcR1 and DcR2 expression are frequently silenced by aberrant methylation of 5Ј regions of these genes in pediatric tumor cell lines and neuroblastomas. In our study, we examined the methylation and expression status of DcR1, DcR2, DR4 and DR5 in breast and lung cancers and malignant mesothelioma (MM).…”

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confidence: 99%

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Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types

Shivapurkar

Toyooka

et al. 2004

Intl Journal of Cancer

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147

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TNF-related apoptosis-inducing ligand (TRAIL) selectively induces programmed cell death (apoptosis) in various cancer cells but not in normal cells. TRAIL is known to bind to 4 different receptors, 2 proapoptotic (DR4 andDR5Several members of the tumor necrosis factor receptor superfamily, which includes tumor necrosis factor receptor 1, Fas (Apo-1/CD95), and the decoy receptors for TRAIL (Apo-2L), regulate programmed cell death (apoptosis). Upon engagement by their respective ligands, tumor necrosis factor receptor 1 and Fas recruit adaptor molecules and activate a cascade of cysteine proteases (caspases), the proteolytic activity of which results in apoptosis. The TRAIL-activated DR4 (also TNFRSF10A, Apo-2, TRAIL-R1) 1,2 and DR5 (also TNFRSF10B, KILLER/DR5, TRICK2, TRAIL-R3) receptors 2-4 have also been shown to initiate a caspase-mediated apoptotic pathway. 4 Death inducing DR4 and DR5 and the decoy receptors DcR1 (also TNFRSF10C, TRID, TRAIL-R3) and DcR2 (also TNFRSF10D, TRUNDD, TRAIL-R4) are structurally related, especially in their extracellular domains and are all located at 8p 21-22. 5,6 Decoy receptor DcR1 completely lacks the intra-cellular death domain and DcR2 contains a truncated, nonfunctional death domain and appear unable to induce apoptosis. The extracellular domains of DcR1 or DcR2 compete with those of DR4 or DR5 for TRAIL binding. Thus, based on the current knowledge, DcR1 or DcR2 are believed to inhibit apoptosis induction mediated through DR4 and DR5. 5 Inactivation of genes may occur via point mutations, allelic loss (LOH), homozygous deletions or by aberrant methylation. 7-9 Aberrant methylation of 5Ј gene promoter regions associated with gene silencing is an epigenetic phenomenon involving many genes observed in almost all cancer types, including breast cancers, lung cancers and mesotheliomas. 9 -18 We have demonstrated loss of expression (at RNA and protein level) of DR4 and DR5 in lung cancer cell lines, although the mechanism was not via methylation. 19 Recently, 20 it was reported that DcR1 and DcR2 expression are frequently silenced by aberrant methylation of 5Ј regions of these genes in pediatric tumor cell lines and neuroblastomas. In our study, we examined the methylation and expression status of DcR1, DcR2, DR4 and DR5 in breast and lung cancers and malignant mesothelioma (MM). We also examined the methylation status of TRAIL receptor genes in many other types of malignancies. We tried to correlate methylation status with clinical features of patients including survival and histological type in lung breast MM and prostate cancer. MATERIAL AND METHODS Cell linesCell lines were initiated by AFG (breast, lung, some MMs) or HIP (most MMs). [21][22][23] Twenty-seven lung cancer cell lines and 23 breast cancer cell lines and were grown in RPMI-1640 medium (Life Technologies Inc., Rockville, MD) supplemented with 5% FBS and incubated in 5% CO 2 at 37°C. Four non-malignant mesothelial primary cell cultures (HCC3466, HCC3468, HCC3469,

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Section: Aberrant Methylation In Cell Linesmentioning

confidence: 84%

Section: Trail Sensitivity Assaymentioning

confidence: 99%

“…Cell survival was quantitated using MTS assay. 19 Sensitivity to TRAIL was measured as percentage survival compared to the untreated controls.…”

Section: Trail Sensitivity Assaymentioning

confidence: 99%

mentioning

confidence: 99%

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Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types

Shivapurkar

Toyooka

et al. 2004

Intl Journal of Cancer

Self Cite

147

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“…The intrinsic pathway involves mitochondria that in response to noxious stimuli release the apoptogenic factors cytochrome c and Smac/DIABLO that activate caspases. It has been shown recently [7][8][9] that in SCLC cells components of the death receptor pathway are silenced by aberrant promoter methylation. Due to impaired death receptor signaling the functional integrity of the mitochondrial pathway is crucial for apoptosis induction in SCLC.…”

mentioning

confidence: 99%

Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation

Belyanskaya¹,

Hopkins-Donaldson²,

Kurtz³

et al. 2005

Intl Journal of Cancer

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The inhibitor of apoptosis protein (IAP) survivin is overexpressed in many tumors but is absent in most normal adult tissues. We report high levels of survivin expression in small cell lung cancer (SCLC), and describe the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in survivin upregulation. Moreover, the cytoprotective function of survivin in response to the anti-cancer agent cisplatin (CDDP) was investigated. Negative modulation of PI3K/ Akt using pharmacological inhibitors or dominant negative Akt (DN-Akt) decreased Akt kinase activity and resulted in decreased survivin expression and phosphorylation on Thr34, whereas transfection of constitutively active Akt (CA-Akt) increased survivin expression and phosphorylation. Interestingly, we found that treatment of SCLC cells with CDDP further increased survivin expression in a cell cycle independent manner by activation of Akt. CA-Akt or lentiviral survivin also inhibited apoptosis induced by CDDP, whereas DN-Akt or survivin-specific RNA interference sensitized cells to CDDP. We identified survivin as an anti-apoptotic protein in SCLC cells that is regulated by Akt, and demonstrate that treatment with the DNA damaging agent CDDP activates the PI3K/Akt/survivin pathway that in part protects cells from drug-induced apoptosis. ' 2005 Wiley-Liss, Inc.

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Caspase 8 is absent or low in many ex vivo gliomas

Ashley

Riffkin

Muscat

et al. 2005

Cancer

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BACKGROUNDBetter treatments are required urgently for patients with malignant glioma, which currently is incurable. Death ligands, such as tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), may offer promise for the treatment high‐grade glioma if such ligands induce apoptotic signaling in vivo in glioma cells. Caspase 8 is required for death ligand signaling, and its levels may influence the sensitivity of glioma cells to death ligands. It also may act as a tumor suppressor protein. The authors analyzed caspase 8 expression levels in ex vivo glioma specimens and explored potential mechanisms of its regulation.METHODSEleven glioblastomas, 5 anaplastic astrocytomas, and 3 low‐grade astrocytomas were studied. The levels of caspase 8, caspase 10, cellular FLICE inhibitory protein (c‐FLIP), and signal transducer and activator of transcription (STAT)‐1 were assayed using quantitative immunoblotting. Caspase 8 mRNA was measured by Northern blot analysis. The methylation status of the caspase 8 gene was determined by bisulfate modification of genomic DNA, cloning, and sequencing. Statistical analyses were performed using nonparametric (Spearman) correlations.RESULTSSome ex vivo glioma samples lacked detectable caspase 8, with many expressing barely detectable levels. No tumors expressed significant amounts of caspase 10 or c‐FLIP. A strong association was found between caspase 8 mRNA and protein levels. Neither expression of the transcription factor STAT‐1 nor caspase 8 gene methylation correlated with caspase 8 levels.CONCLUSIONSThe absence of caspase 8 protein in many resected glioma samples implied that many patients with glioma may not benefit from death ligand‐based treatments, unless caspase 8 (or caspase 10) protein expression can be elevated. Demethylating agents are unlikely to boost caspase 8 levels in glioma cells, but treatments that increase caspase 8 mRNA levels may up‐regulate expression of the protein. Cancer 2005. © 2005 American Cancer Society.

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Loss of expression of death-inducing signaling complex (DISC) components in lung cancer cell lines and the influence of MYC amplification

Cited by 67 publications

References 24 publications

Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types

Aberrant methylation of trail decoy receptor genes is frequent in multiple tumor types

Cisplatin activates Akt in small cell lung cancer cells and attenuates apoptosis by survivin upregulation

Caspase 8 is absent or low in many ex vivo gliomas

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