Apoptotic Signaling in Pancreatic Cancer – Therapeutic Application (Supplemental Data)

Rückert, Felix; Pilarsky, Christian; Saeger, Hans‐Detlev; Grützmann, Robert

doi:10.2174/157339409788166760

Cited by 4 publications

(6 citation statements)

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“…Defects in apoptosis are important for different clinicopathologic attributes of PDAC, such as ability to metastasize, resistance toward chemotherapy, and promotion of further neoplastic progression by attenuation of the deletion of genetically damaged cells from organs [23]. Dysregulation of genes associated with the intrinsic apoptotic pathway seem to play an important role in mediating this resistance to apoptosis [24,25].…”

Section: Discussionmentioning

confidence: 99%

Five Primary Human Pancreatic Adenocarcinoma Cell Lines Established by the Outgrowth Method

Rückert¹,

Aust²,

Böhme³

et al. 2012

Journal of Surgical Research

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Section: Discussionmentioning

confidence: 99%

Five Primary Human Pancreatic Adenocarcinoma Cell Lines Established by the Outgrowth Method

Rückert¹,

Aust²,

Böhme³

et al. 2012

Journal of Surgical Research

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“…Apoptosis resistance in pancreatic cancer is highly relevant for the aggressive nature of the disease. Previous studies in pancreatic cancer have described multiple defects in apoptosis signaling at different levels of the pathway [ 8 , 23 , 24 ]. Based on the concept of apoptotic thresholds [ 9 ], we hypothesized that there might be a benefit in hitting multiple target genes at the same time rather than individual genes to achieve an effect on tumor survival.…”

Section: Discussionmentioning

confidence: 99%

“…The 'extrinsic' cell death pathway is activated through death receptors. Many physiological control points protect the cell from inappropriate apoptosis induction [ 8 ]. The net balance of all pro-and anti-apoptotic "control mechanisms" determines the apoptotic threshold of the cell.…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous gene silencing of Bcl-2, XIAP and Survivin re-sensitizes pancreatic cancer cells towards apoptosis

et al. 2010

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BackgroundPancreatic ductal adenocarcinoma shows a distinct apoptosis resistance, which contributes significantly to the aggressive nature of this tumor and constrains the effectiveness of new therapeutic strategies. Apoptosis resistance is determined by the net balance of the cells pro-and anti-apoptotic "control mechanisms". Numerous dysregulated anti-apoptotic genes have been identified in pancreatic cancer and seem to contribute to the high anti-apoptotic buffering capacity. We aimed to compare the benefit of simultaneous gene silencing (SGS) of several candidate genes with conventional gene silencing of single genes.MethodsFrom literature search we identified the anti-apoptotic genes XIAP, Survivin and Bcl-2 as commonly upregulated in pancreatic cancer. We performed SGS and silencing of single candidate genes using siRNA molecules in two pancreatic cancer cell lines. Effectiveness of SGS was assessed by qRT-PCR and western blotting. Apoptosis induction was measured by flow cytometry and caspase activation.ResultsSimultaneous gene silencing reduced expression of the three target genes effectively. Compared to silencing of a single target or control, SGS of these genes resulted in a significant higher induction of apoptosis in pancreatic cancer cells.ConclusionsIn the present study we performed a subliminal silencing of different anti-apoptotic target genes simultaneously. Compared to silencing of single target genes, SGS had a significant higher impact on apoptosis induction in pancreatic cancer cells. Thereby, we give further evidence for the concept of an anti-apoptotic buffering capacity of pancreatic cancer cells.

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“…Apoptosis, or cell death program, can be activated by various mechanisms within the extrinsic and the intrinsic pathway. While activation of cell death receptors leads to the engagement of the extrinsic pathway, the intrinsic pathway is activated by mitochondria during cellular stress, both resulting in an activation of caspases [8] .…”

Section: Introductionmentioning

confidence: 99%

Examination of Apoptosis Signaling in Pancreatic Cancer by Computational Signal Transduction Analysis

et al. 2010

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BackgroundPancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer death. Changes in apoptosis signaling in pancreatic cancer result in chemotherapy resistance and aggressive growth and metastasizing. The aim of this study was to characterize the apoptosis pathway in pancreatic cancer computationally by evaluation of experimental data from high-throughput technologies and public data bases. Therefore, gene expression analysis of microdissected pancreatic tumor tissue was implemented in a model of the apoptosis pathway obtained by computational protein interaction prediction.Methodology/Principal FindingsApoptosis pathway related genes were assembled from electronic databases. To assess expression of these genes we constructed a virtual subarray from a whole genome analysis from microdissected native tumor tissue. To obtain a model of the apoptosis pathway, interactions of members of the apoptosis pathway were analysed using public databases and computational prediction of protein interactions. Gene expression data were implemented in the apoptosis pathway model. 19 genes were found differentially expressed and 12 genes had an already known pathophysiological role in PDAC, such as Survivin/BIRC5, BNIP3 and TNF-R1. Furthermore we validated differential expression of IL1R2 and Livin/BIRC7 by RT-PCR and immunohistochemistry. Implementation of the gene expression data in the apoptosis pathway map suggested two higher level defects of the pathway at the level of cell death receptors and within the intrinsic signaling cascade consistent with references on apoptosis in PDAC. Protein interaction prediction further showed possible new interactions between the single pathway members, which demonstrate the complexity of the apoptosis pathway.Conclusions/SignificanceOur data shows that by computational evaluation of public accessible data an acceptable virtual image of the apoptosis pathway might be given. By this approach we could identify two higher level defects of the apoptosis pathway in PDAC. We could further for the first time identify IL1R2 as possible candidate gene in PDAC.

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Apoptotic Signaling in Pancreatic Cancer – Therapeutic Application (Supplemental Data)

Cited by 4 publications

References 151 publications

Five Primary Human Pancreatic Adenocarcinoma Cell Lines Established by the Outgrowth Method

Five Primary Human Pancreatic Adenocarcinoma Cell Lines Established by the Outgrowth Method

Simultaneous gene silencing of Bcl-2, XIAP and Survivin re-sensitizes pancreatic cancer cells towards apoptosis

Examination of Apoptosis Signaling in Pancreatic Cancer by Computational Signal Transduction Analysis

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