Nutlin-3 inhibits the NFκB Pathway in a p53 Dependent Manner: Implications in Lung Cancer Therapy

Dey, Anwesha; Wong, Ee Tsin; Bist, Pradeep; Tergaonkar, Vinay; Lane, David P.

doi:10.4161/cc.6.17.4643

Cited by 62 publications

(43 citation statements)

References 48 publications

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“…The decrease in the proinflammatory responses of nutlin-3a-treated cells to LPS was not caused by cell death since nutlin-3a did not induce any apparent alteration in apoptosis among either neutrophils or macrophages after 4 h of treatment. Furthermore, nutlin-3a exposure did not alter proximal signaling events, such as activation of MAPK and IKK, after TLR4 engagement, which is consistent with the findings by Dey et al (49) that nutlin-3a does not affect TNF-␣-or IL-1-induced IB-␣ phosphorylation and degradation or p65 phosphorylation in cancer cells. However, nutlin-3a treatment did inhibit the binding of NF-B to promoters of target genes in LPS-treated macrophages and neutrophils.…”

Section: Discussionsupporting

confidence: 90%

p53 Attenuates Lipopolysaccharide-Induced NF-κB Activation and Acute Lung Injury

Liu

Park

Tsuruta

et al. 2009

The Journal of Immunology

124

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The transcriptional factor p53 has primarily been characterized for its central role in the regulation of oncogenesis. A reciprocal relationship between the activities of p53 and NF-B has been demonstrated in cancer cells, but there is little information concerning interactions between p53 and NF-B in inflammatory processes. In this study, we found that neutrophils and macrophages lacking p53, i.e., p53

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Section: Discussionsupporting

confidence: 90%

p53 Attenuates Lipopolysaccharide-Induced NF-κB Activation and Acute Lung Injury

Liu

Park

Tsuruta

et al. 2009

The Journal of Immunology

124

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“…It was shown previously in vitro that Nutlin-3A can down-regulate TNFα-and IL-1-induced activation of NF-κB-dependent reporter gene expression and inhibit the expression of proteins encoded by the NF-κB target genes ICAM-1 and MCP-1, which are known to be critical for cancer cell invasion. 102 In our in vivo experiments, mice given Nutlin-3A by gavage showed significantly reduced serum levels of cytokines, including IL-1β, IL-6, TNFα, and GM-CSF (E. A. Komarova, L. Vassilev, and A. V. Gudkov, in preparation).…”

Section: Monographsmentioning

confidence: 78%

Inflammation and p53: A Tale of Two Stresses

Gudkov

Gurova²,

Komarova³

2011

Genes & Cancer

171

145

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Numerous observations indicate a strong link between chronic inflammation and cancer. This link is supported by substantial experimental evidence indicating mutual negative regulation of NF-κB, the major regulator of inflammation, and p53, the major tumor suppressor. This antagonistic relationship reflects the opposite principles of the physiological responses driven by these transcription factors, which act as sensors and mediators of intrinsic and extrinsic cell stresses, respectively. Constitutive activation of NF-κB, the underlying cause of chronic inflammation, is a common acquired characteristic of tumors. A variety of experimental methods have been used to demonstrate that constitutive activation of NF-κB reduces the tumor suppressor activity of p53, thereby creating permissive conditions for dominant oncogene-mediated transformation. Loss of p53 activity is also a characteristic of the majority of tumors and results in unleashed inflammatory responses due to loss of p53-mediated NF-κB suppression. On the other hand, in natural or pharmacological situations of enforced p53 activation, NF-κB activity, inflammation, and immune responses are reduced, resulting in different pathologies. It is likely that the chronic inflammation that is commonly acquired in various tissues of older mammals leads to general suppression of p53 function, which would explain the increased risk of cancer observed in aging animals and humans. Although the molecular mechanisms underlying reciprocal negative regulation of p53 and NF-κB remain to be deciphered, this phenomenon has important implications for pharmacological prevention of cancer and aging and for new approaches to control inflammation.

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“…Taking into account that OPG is an NF-B-dependent gene and that a molecular cross-talk between the p53 and NF-B pathways has been established, 28,29 the next experiments were carried out to evaluate whether Nutlin-3 down-regulated OPG expression/release by modulating the NF-B pathway. This was initially investigated by assessing the modulation of the human OPG promoter, containing consensus NF-B sites, in functional assays ( Figure 6A).…”

Section: Nutlin-3 Inhibits Tnf-␣-induced Nf-b Recruitment To the Opg mentioning

confidence: 99%

Activation of the p53 pathway down-regulates the osteoprotegerin expression and release by vascular endothelial cells

Secchiero

Corallini

Rimondi

et al. 2008

Blood

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IntroductionOsteoprotegerin (OPG) is a soluble member of the tumor necrosis factor (TNF) receptor superfamily, whose best characterized activity is the inhibition of receptor activator of NF-B ligand (RANKL)-stimulated formation of osteoclasts. 1 OPG also interacts with TNF-related apoptosis-inducing ligand (TRAIL), 2 a deathinducing ligand whose extracellular domain shares a 35% homology with RANKL. Mounting evidence indicates that the ability of OPG to inhibit TRAIL cytotoxicity might represent an important mechanism in promoting the survival of prostate cancer, breast cancer, colon cancer, and multiple myeloma cells at least in vitro. [3][4][5] More importantly, for the purpose of this study, it has also been shown that OPG is produced in vitro by vascular endothelial cells, is overexpressed by tumor-associated endothelial cells, and is able to promote the survival/proliferation of endothelial cells in a paracrine or autocrine manner. [6][7][8][9][10] Moreover, elevated levels of serum OPG have been detected in both solid tumors and hematologic malignancies. 11 Although the relative contribution of both normal and tumor-associated endothelial cells to serum OPG remains to be established, 2 both the stromal and the tumoral vasculature is engaged in extensive interactions with the cancer cells, probably contributing to the growth and invasiveness of the tumor. 12,13 The p53 protein is a sequence-specific transcription factor that functions as a major tumor suppressor in mammals. 13,14 In response to various types of oncogenic stresses, p53 is activated to promote cell-cycle exit, apoptosis, or replicative senescence, thereby preventing the propagation of incipient cancer cells.Consequently, p53 is very often disabled within cancer cells, either by direct mutational inactivation of the TP53 gene or by alterations in other genes of which the products impinge on p53. Whereas the effect of p53 has been widely investigated in a cell-autonomous context, much less attention has been given to its non-cell-autonomous functions, although it has been recently demonstrated that the stromal compartment of the tumors is able to modulate the latency of tumorigenesis in a p53-dependent manner. 12,13 On these bases, the aim of this study was to investigate the effect of p53 knock-down and/or induction on the expression and release of OPG in human endothelial cells. Methods Cell cultures and treatmentsHuman umbilical vein endothelial cells (HUVECs) were purchased from BioWhittaker (Walkersville, MD) and grown on 0.2% gelatin-coated tissue culture plates in M199 endothelial growth medium supplemented with 20% fetal bovine serum, 10 g/mL heparin, and 50 g/mL ECGF (endothelial cell growth factor; all from BioWhittaker). In all experiments, cells were used between the 3rd and 5th passages in vitro, as previously described. 15 For endothelial cell treatments, the following reagents have been used: Nutlin-3 (Cayman Chemical, Ann Arbor, MI), TNF-␣ (R&D Systems, Minneapolis, MN), and Aphidicolin (Alexis Biochemicals, Lausen, Switzerland...

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Nutlin-3 inhibits the NFκB Pathway in a p53 Dependent Manner: Implications in Lung Cancer Therapy

Cited by 62 publications

References 48 publications

p53 Attenuates Lipopolysaccharide-Induced NF-κB Activation and Acute Lung Injury

p53 Attenuates Lipopolysaccharide-Induced NF-κB Activation and Acute Lung Injury

Inflammation and p53: A Tale of Two Stresses

Activation of the p53 pathway down-regulates the osteoprotegerin expression and release by vascular endothelial cells

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