Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis

Stathopoulos, Georgios T.; Sherrill, Taylor P.; Cheng, Dong-Sheng; Scoggins, Robert M.; Han, Wei; Polosukhin, Vasiliy V.; Connelly, Linda; Yull, Fiona E.; Fingleton, Barbara; Blackwell, Timothy S.

doi:10.1073/pnas.0705316104

Cited by 182 publications

(257 citation statements)

References 49 publications

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“…Our recent work has revealed that nuclear RelA and cytoplasmic pI-κBα are significantly associated with a poor prognosis in cancer (10). Furthermore, chemotherapy-induced activation of NF-κB can blunt the ability of the chemotherapy itself to induce cell death in lung cancer cells (11,12). NF-κB is involved in the regulation of transcription of various genes involved in cell proliferation, angiogenesis, metastasis, and apoptosis (13,14), which seems to lie at the heart of the ability of NF-κB to promote cancer therapy resistance.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

Zhang

Qiu²,

Jin³

et al. 2009

Molecular Cancer Research

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In this study, we have examined the molecular events induced by parthenolide, a sesquiterpene lactone, and explored possible mechanisms of resistance and sensitization of tumor cells to Taxol. We showed that parthenolide could antagonize Taxol-mediated nuclear factor-κB (NF-κB) nuclear translocation and activation and Bcl-xl up-regulation by selectively targeting I-κB kinase activity. In A549 cells, inhibition of nuclear factor-κB by parthenolide resulted in activation of the mitochondrial death pathway to promote cytochrome c release and caspase 3 and 9 activation. In contrast, Taxol alone induced apoptosis via a pathway independent of mitochondria cytochrome c cascade. In addition, depletion of Bcl-xl rescued the apoptotic response to Taxol. Moreover, treatment with parthenolide increased the efficacy of the Taxol-induced inhibition of A549 tumor xenografts in mice. This study elucidated the cellular responses induced by parthenolide that decrease the threshold of mitochodriadependent apoptosis in the treatment of non-small cell lung cancer cells.

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Section: Introductionmentioning

confidence: 99%

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

Zhang

Qiu²,

Jin³

et al. 2009

Molecular Cancer Research

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“…In mouse models of urethane-induced and KRASdriven lung cancers, inhibition of canonical NF-kB increased apoptosis and/or reduced epithelial cell proliferation, [10][11][12]30 although whether these findings are a direct or indirect effect of NF-kB inhibition is unclear. Supporting our findings, others have reported that NF-kB inhibition did not affect proliferation of human lung cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…7 In KRAS-mediated lung tumorigenesis, as well as in mouse models of chemical carcinogen-induced lung cancer, NF-kB plays an important role in tumorigenesis. [9][10][11][12] EGFR signaling is known to activate NF-kB in a variety of tumor types, 13,14 and NF-kB signaling has been shown to facilitate resistance to EGFR inhibitor therapies in lung cancer. [15][16][17][18] However, the importance of the NF-kB pathway during oncogenic EGFR-driven lung tumorigenesis has not been examined.…”

Section: Introductionmentioning

confidence: 99%

Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment

et al. 2016

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Several studies have demonstrated that NF-kB activation is common in lung cancer; however, the mechanistic links between NF-kB signaling and tumorigenesis remain to be fully elucidated. We investigated the function of NF-kB signaling in epidermal growth factor receptor (EGFR)-mutant lung tumors using a transgenic mouse model with doxycycline (dox)-inducible expression of oncogenic EGFR in the lung epithelium with or without a dominant inhibitor of NF-kB signaling. NF-kB inhibition resulted in a significant reduction in tumor burden in both EGFR tyrosine kinase inhibitor (TKI)-sensitive and resistant tumors. However, NF-kB inhibition did not alter epithelial cell survival in vitro or in vivo, and no changes were detected in activation of EGFR downstream signaling pathways. Instead, we observed an influx of inflammatory cells (macrophages and neutrophils) in the lungs of mice with oncogenic EGFR expression that was blocked in the setting of NF-kB inhibition. To investigate whether inflammatory cells play a role in promoting EGFR-mutant lung tumors, we depleted macrophages and neutrophils during tumorigenesis and found that neutrophil depletion had no effect on tumor formation, but macrophage depletion caused a significant reduction in tumor burden. Together, these data suggest that epithelial NFkB signaling supports carcinogenesis in a non-cell autonomous manner in EGFR-mutant tumors through recruitment of pro-tumorigenic macrophages.

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“…Finally, the NGL transgenic reporter mice used here and the similarly functioning HLL reporter mice 17 have been used in numerous studies to verify, quantify, and track the up or down regulation of NF-κB activity within a variety of disease and developmental models including acute lung injury, lung cancer, airway branching morphogenesis, insulin resistance, obesity, and myocardial infarction 1,[17][18][19][20][21] . This model provides an additional example of the utility of these reporter transgenics.…”

Section: It Is Clear Frommentioning

confidence: 99%

Intraductal Injection of LPS as a Mouse Model of Mastitis: Signaling Visualized via an NF-κB Reporter Transgenic

Barham

Sherrill

Connelly

et al. 2012

JoVE

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Animal models of human disease are necessary in order to rigorously study stages of disease progression and associated mechanisms, and ultimately, as pre-clinical models to test interventions. In these methods, we describe a technique in which lipopolysaccharide (LPS) is injected into the lactating mouse mammary gland via the nipple, effectively modeling mastitis, or inflammation, of the gland. This simulated infection results in increased nuclear factor kappa B (NF-κB) signaling, as visualized through bioluminescent imaging of an NF-κB luciferase reporter mouse 1 .Our ultimate goal in developing these methods was to study the inflammation associated with mastitis in the lactating gland, which often includes redness, swelling, and immune cell infiltration 2,3 . Therefore, we were keenly aware that incision or any type of wounding of the skin, the nipple, or the gland in order to introduce the LPS could not be utilized in our methods since the approach would likely confound the read-out of inflammation. We also desired a straight-forward method that did not require specially made hand-drawn pipettes or the use of micromanipulators to hold these specialized tools in place. Thus, we determined to use a commercially available insulin syringe and to inject the agent into the mammary duct of an intact nipple. This method was successful and allowed us to study the inflammation associated with LPS injection without any additional effects overlaid by the process of injection. In addition, this method also utilized an NF-κB luciferase reporter transgenic mouse and bioluminescent imaging technology to visually and quantitatively show increased NF-κB signaling within the LPS-injected gland 4 .These methods are of interest to researchers of many disciplines who wish to model disease within the lactating mammary gland, as ultimately, the technique described here could be utilized for injection of a number of substances, and is not limited to only LPS. Video LinkThe video component of this article can be found at

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Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis

Abstract: apoptosis ͉ cancer ͉ inflammation ͉ airway ͉ adenocarcinoma

Cited by 182 publications

References 49 publications

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment

Intraductal Injection of LPS as a Mouse Model of Mastitis: Signaling Visualized via an NF-κB Reporter Transgenic

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Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis

Abstract: apoptosis ͉ cancer ͉ inflammation ͉ airway ͉ adenocarcinoma

Cited by 182 publications

References 49 publications

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment

Intraductal Injection of LPS as a Mouse Model of Mastitis: Signaling Visualized via an NF-&kappa;B Reporter Transgenic

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Intraductal Injection of LPS as a Mouse Model of Mastitis: Signaling Visualized via an NF-κB Reporter Transgenic