CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-κB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells

Trauzold, Anna; Wermann, Hendrik; Arlt, Alexander; Schütze, Stefan; Schäfer, Heiner; Oestern, Stefanie; Röder, Christian; Ungefroren, Hendrik; Lampe, Esther; Heinrich, Michael; Walczak, Henning; Kalthoff, Holger

doi:10.1038/sj.onc.1204559

Cited by 158 publications

(138 citation statements)

References 37 publications

(39 reference statements)

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“…Since it was shown (Hinz et al, 2000;Trauzold et al, 2001) that pancreatic tumour cell lines behave like type II cells in both, CD95-and TRAIL-mediated apoptosis, we did not only analyse the expression levels of caspases and DISC components, but also of proteins which participate in the mitochondrial apoptosis pathway (Werner et al, 2002). Therefore, we additionally analysed the expression of Bfl-1.…”

Section: Expression Of Apoptosis-relevant Proteins In Pancreatic Adenmentioning

confidence: 99%

“…Pancreatic carcinoma cells are regarded as type II cells in which only small amounts of active caspase-8 are generated at the DISC and a mitochondrial amplification loop is necessary for proper apoptosis induction (Hinz et al, 2000;Trauzold et al, 2001;Ungefroren et al, 2001).…”

Section: Badmentioning

confidence: 99%

“…The majority of pancreatic adenocarcinoma cell lines is resistant to CD95 and TRAIL-mediated apoptosis despite expressing the corresponding death receptors at the cell surface (Ungefroren et al, 1998;Trauzold et al, 2001). Recently, we revealed an anti-apoptotic role of constitutively overexpressed FAP-1 and Bcl-x L (Hinz et al, 2000) in these cells.…”

mentioning

confidence: 92%

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Multiple and synergistic deregulations of apoptosis-controlling genes in pancreatic carcinoma cells

et al. 2003

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Inability to die by apoptosis is one of the reasons for the deregulated growth of tumour cells and the frequently observed failure of chemotherapy. In this study we thought to identify the common and functionally important characteristics responsible for the apoptosis resistance of pancreatic tumour cells. We analysed cell surface expression level of death receptors CD95 and TRAIL-R1-4 as well as the expression profile of sixteen apoptosis-relevant proteins in five pancreatic carcinoma cell lines Capan1, Colo357, PancTuI, Panc89 and Panc1. These data were evaluated in the context of sensitivity towards anti-CD95 and TRAIL-mediated apoptosis. Here we report that except for resistant Panc1 cells, which only marginally expressed CD95, all other cell lines showed comparable levels of CD95 and TRAIL receptors irrespectively of their apoptotic phenotype. Interestingly, we found that the elevated expression of FLIP, Bcl-x L and IAP in parallel with a downregulation of FADD and Bid was common for the resistant cell lines. Consequently, stable overexpression of XIAP, Bcl-x L or dominant negative FADD in sensitive cells significantly reduced the death receptor mediated apoptosis while the overexpression of Bid rendered the resistant cells sensitive.

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Section: Expression Of Apoptosis-relevant Proteins In Pancreatic Adenmentioning

confidence: 99%

Section: Badmentioning

confidence: 99%

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Multiple and synergistic deregulations of apoptosis-controlling genes in pancreatic carcinoma cells

et al. 2003

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“…The stimulation of the CD95-and TRAIL-resistant human pancreatic adenocarcinoma cell line, Panc TuI, with an agonistic anti-CD95 antibody or TRAIL activates protein kinase C and NF-κB. The activation of PKC operates directly in a death receptor dependent manner in PancTuI cells and pancreatic tumor cells, protecting them from anti-CD95 and TRAIL-mediated apoptosis by preventing the loss of DeltaPsim and cytochrome c release, as well as by the induction of NF-κB (Trauzold et al, 2001). Pharmacologic or molecular inhibition of the NF-κB pathway blocked cell survival in MCF-7 APO+ cells, while only molecular inhibition induced cytotoxicity in the APO-cells (Weldon et al, 2001).…”

Section: Anti-apoptotic Effects Of Nf-κbmentioning

confidence: 99%

Nuclear Factor-κB Activation: A Question of Life or Death

Shishodia¹,

Aggarwal²

2002

BMB Reports

206

168

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Apoptosis is a mode of cell death that plays an important role in both pathological and physiological processes. Research during the last decade has delineated the entire machinery needed for cell death, and its constituents were found to pre-exist in cells. The apoptotic cascade is triggered when cells are exposed to an apoptotic stimulus. It has been known for several years that inhibitors of protein synthesis can potentiate apoptosis that is induced by cytokines and other inducers. Until 1996, it was not understood why protein synthesis inhibitors potentiate apoptosis. Then three reports appeared that suggested the role of the transcription factor NF-κB activation in protecting the cells from TNF-induced apoptosis. Since then several proteins have been identified that are regulated by NF-κB and are involved in cell survival, proliferation, and protection from apoptosis. It now seems that when a cell is attacked by an apoptotic stimulus, the cell responds first by activating anti-apoptotic mechanisms, which may or may not be followed by apoptosis. Whether or not a cell undergoes proliferation, the survival, or apoptosis, appears to involve a balance between the two mechanisms. Inhibitors of protein synthesis seem to suppress the appearance of protein that are involved in anti-apoptosis. The present review discusses how NF-κB controls apoptosis.

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“…Increasingly it is being realized that TRAIL induced pro-survival signals in pancreatic cancer cells as evidenced byactivation of protein kinase C and NF-kappaB in TRAIL treated pancreatic adenocarcinoma cell line PancTuI. Synthetic agent mediated inhibition of NF-kappaB or transient transfection with a dominant negative mutant of IkappaBalpha induced apoptosis in TRAIL treated cancer cells (Trauzold et al, 2001). NEMO-binding domain (NBD) peptide is a novel selective NF-kappaB inhibitor and results revealed that NBD treated L3.6 cell line (TRAIL resistant) displayed TRAIL induced apoptosis (Thomas et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

TRAIL Mediated Signaling in Pancreatic Cancer

Nogueira

Yaylım²,

Aamir³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Research over the years has progressively shown substantial broadening of the tumor necrosis factor alpharelated apoptosis-inducing ligand (TRAIL)-mediated signaling landscape. Increasingly it is being realized that pancreatic cancer is a multifaceted and genomically complex disease. Suppression of tumor suppressors, overexpression of oncogenes, epigenetic silencing, and loss of apoptosis are some of the extensively studied underlying mechanisms. Rapidly accumulating in vitro and in vivo evidence has started to shed light on the resistance mechanisms in pancreatic cancer cells. More interestingly a recent research has opened new horizons of miRNA regulation by DR5 in pancreatic cancer cells. It has been shown that DR5 interacts with the core microprocessor components Drosha and DGCR8, thus impairing processing of primary let-7. Xenografting DR5 silenced pancreatic cancer cells in SCID-mice indicated that there was notable suppression of tumor growth. There is a paradigm shift in our current understanding of TRAIL mediated signaling in pancreatic cancer cells that is now adding new layers of concepts into the existing scientific evidence. In this review we have attempted to provide an overview of recent advances in TRAIL mediated signaling in pancreatic cancer as evidenced byfindings of in vitro and in vivo analyses. Furthermore, we discuss nanotechnological advances with emphasis on PEG-TRAIL and four-arm PEG cross-linked hyaluronic acid (HA) hydrogels to improve availability of TRAIL at target sites.

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CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-κB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells

Cited by 158 publications

References 37 publications

Multiple and synergistic deregulations of apoptosis-controlling genes in pancreatic carcinoma cells

Multiple and synergistic deregulations of apoptosis-controlling genes in pancreatic carcinoma cells

Nuclear Factor-κB Activation: A Question of Life or Death

TRAIL Mediated Signaling in Pancreatic Cancer

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