Constitutively Activated Nuclear Factor-κB, but not Induced NF-κB, Leads to TRAIL Resistance by Up-Regulation of X-Linked Inhibitor of Apoptosis Protein in Human Cancer Cells

Braeuer, S.; Büneker, Chirlei; Mohr, Andrea; Zwacka, Ralf M.

doi:10.1158/1541-7786.mcr-05-0231

Cited by 80 publications

(68 citation statements)

References 97 publications

(118 reference statements)

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“…Nuclear factor-kB has been reported to be activated in various tumours, such as human leukaemia and lymphoma, the lung, breast, colon and pancreatic carcinomas (Rayet and Gelinas, 1999;Karin and Lin, 2002;Wu and Kral, 2005;Braeuer et al, 2006). The p65 subunit of NF-kB is constitutively activated in most human pancreatic cancer tissues and cell lines (Wang et al, 1999), and this activation has been shown to have important functions in tumourigenesis and liver metastasis of pancreatic adenocarcinoma (Fujioka et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Role of reactive oxygen species in brucein D-mediated p38-mitogen-activated protein kinase and nuclear factor-κB signalling pathways in human pancreatic adenocarcinoma cells

2010

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BACKGROUND: In human pancreatic adenocarcinoma, nuclear factor-kappa-B (NF-kB) transcription factor is constitutively activated that contributes to the resistance of the tumour cells to induced apoptosis. In our earlier studies, we have shown that brucein D (BD) mediated apoptosis through activation of the p38-mitogen-activated protein kinase (MAPK) signalling pathway in pancreatic cancer cells. This study investigated the function of reactive oxygen species (ROS) in BD-mediated p38-MAPK and NF-kB signalling pathways in PANC-1 cells. METHODS: Glutathione and dihydroethidium assays were used to measure the antioxidant and superoxide levels, respectively. The protein expression of p22 phox , p67 phox and p38-MAPK were examined by western blot. The NF-kB activity was evaluated by electrophoretic mobility shift assay. RESULTS: Treatment with BD depleted the intracellular glutathione levels in PANC-1 cells. Brucein D triggered the activation of NADPH oxidase isoforms, p22 phox and p67 phox while enhancing the generation of superoxide. Increases in both intracellular ROS and NADPH oxidase activity were inhibited by an antioxidant, N-acetylcysteine (NAC). Brucein D-mediated activation of p38-MAPK was also inhibited by NAC. However, inhibition of NF-kB activity in BD-treated cells was independent of ROS. In vivo studies showed that BD treatment effectively reduced the rate of xenograft human pancreatic tumour in nude mice with no significant toxicity. CONCLUSION: These data suggest that BD is an apoptogenic agent for pancreatic cancer cells through activation of the redox-sensitive p38-MAPK pathway and inhibition of NF-kB anti-apoptotic activity in pancreatic cancer cells.

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Section: Discussionmentioning

confidence: 99%

Role of reactive oxygen species in brucein D-mediated p38-mitogen-activated protein kinase and nuclear factor-κB signalling pathways in human pancreatic adenocarcinoma cells

2010

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“…Because XIAP overexpression has been identified as a critical factor in TRAIL resistance [15,42,43], we wanted to delineate the role of XIAP expression in sensitivity to Smac mimetics. To do this, we characterized both Birinapant and GT13402, which have differential affinity for XIAP, in SUM149…”

Section: Smac Mimetic Enhances Trail Potency In a Trail-sensitive Ibcmentioning

confidence: 99%

Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism

Allensworth

Sauer

Lyerly

et al. 2012

Breast Cancer Res Treat

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Abstract:X-linked Inhibitor of Apoptosis Protein (XIAP), the most potent mammalian caspase inhibitor, has been associated with acquired therapeutic resistance in inflammatory breast cancer (IBC), an aggressive subset of breast cancer with an extremely poor survival rate. The second mitochondria-derived activator of caspases (Smac) protein is a potent antagonist of IAP proteins and the basis for the development of Smac mimetic drugs. Here, we report for the first time that bivalent Smac mimetic Birinapant induces cell death as a single agent in TRAIL-insensitive SUM190 (ErbB2-overexpressing) cells and significantly increases potency of TRAIL-induced apoptosis in TRAILsensitive SUM149 (triple negative, EGFR-activated) cells, two patient tumor-derived IBC models. Birinapant has high binding affinity (nM range) for cIAP1/2 and XIAP. Using isogenic SUM149-and SUM190-derived cells with differential XIAP expression (SUM149 wtXIAP, SUM190 shXIAP) and another bivalent Smac mimetic (GT13402) with high cIAP1/2 but low XIAP binding affinity (Kd >1 µM), we show that XIAP inhibition is necessary for increasing TRAIL potency. In contrast, single agent efficacy of Birinapant is due to pan-IAP antagonism. Birinapant caused rapid cIAP1 degradation, caspase activation, PARP cleavage, and NF-κB activation. A modest increase in TNF-α production was seen in SUM190 cells following Birinapant treatment, but no increase occurred in SUM149 cells. Exogenous TNF-α addition did not increase Birinapant efficacy. Neutralizing antibodies against TNF-α or TNFR1 knockdown did not reverse cell death. However, pan-caspase inhibitor Q-VD-OPh reversed Birinapant-mediated cell death. In addition, Birinapant in combination or as a single agent decreased colony formation and anchorage-independent growth potential of IBC cells. The above manuscript was initially submitted to Breast Cancer Research and Treatment and the authors received the reviews along with the decision of 'could be accepted for publication should you be prepared to incorporate major revisions'.We thank the reviewer for his recommendations that were indeed helpful in revising this manuscript. We have included a detailed author response and revision status of each of the reviewer's comments.In response to the reviewer's concerns, we have undertaken the following experiments: 1.Measurement of clonogenic growth potential as a means of assessing viability effects of the Smac mimetic treatments 2.Annexin-V/7-AAD flow cytometric staining of cells treated with the Smac mimetics as a direct means of evaluating apoptosis 3.An in-depth time course analysis of NF-kB activation in SUM190 cells following treatment with the Smac mimetic 4.Assessment of anchorage independent growth potential as a preliminary predictor of in vivo activity of the Smac mimeticWe sincerely hope that all the reviewers' concerns have been adequately addressed and the manuscript is acceptable for publication in the present revised form.Disclosure Statement: The authors are aware of and agree to the content of the paper and ...

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“…Panc-1 cells have constitutively activated NFKB and it has been experimentally verified that introduction of IκB-α superrepressor considerably reduced NF-kB DNA-binding activity (Braeuer et al, 2006). Shikonin, a naphthoquinone derivative has been shown to repress constitutive as well as gemcitabine-induced activation of NF-kB and NF-kBtarget genes.…”

Section: Molecular Basis Of Trail Resistancementioning

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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Constitutively Activated Nuclear Factor-κB, but not Induced NF-κB, Leads to TRAIL Resistance by Up-Regulation of X-Linked Inhibitor of Apoptosis Protein in Human Cancer Cells

Cited by 80 publications

References 97 publications

Role of reactive oxygen species in brucein D-mediated p38-mitogen-activated protein kinase and nuclear factor-κB signalling pathways in human pancreatic adenocarcinoma cells

Role of reactive oxygen species in brucein D-mediated p38-mitogen-activated protein kinase and nuclear factor-κB signalling pathways in human pancreatic adenocarcinoma cells

Smac mimetic Birinapant induces apoptosis and enhances TRAIL potency in inflammatory breast cancer cells in an IAP-dependent and TNF-α-independent mechanism

TRAIL Mediated Signaling in Pancreatic Cancer

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