Overexpression of phosphorylated nuclear factor-kappa B in tonsillar squamous cell carcinoma and high-grade dysplasia is associated with poor prognosis

Zhang, Ping L.; Pellitteri, Phillip K.; Law, Amy; Gilroy, Patricia A; Wood, G. Craig; Kennedy, Thomas L.; Blasick, Thomas M.; Lun, Mingyue; Schuerch, Conrad; Brown, Robert E.

doi:10.1038/modpathol.3800372

Cited by 53 publications

(57 citation statements)

References 30 publications

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“…To examine the sensitivity of HNSCC to HDIs, we examined a panel of six HNSCC lines from the University of Michigan series (UMSCC). The UMSCC-1, UMSCC-6, UMSCC-9, UMSCC-11A, UMSCC-11B, and UMSCC-38 cell lines have previously been extensively characterized and found to exhibit varying levels of constitutive NF-nB activation (10,30), consistent with variation observed in tumor specimens from patients (31). NF-nB DNA binding and luciferase activity in UMSCC-1, UMSCC-6, UMSCC-11A, and UMSCC-11B is 1-to 3-fold greater than that of UMSCC-9 and UMSCC-38 (30).…”

Section: Limited Inhibitory Effects Of Hdis In Umscc Cells With Basalmentioning

confidence: 69%

“…1C above, we examined if HDIs increased nuclear DNA binding activity and acetylation of NF-nB1/RelA p50/p65, the species of NF-nB detected previously in HNSCC cell lines (10) and tumor specimens (24,31). The UMSCC-11A and UMSCC-11B cell lines selected for further molecular analysis were shown previously to exhibit DNA binding activity composed of p50/p65 heterodimers (10) and intermediate levels of NF-nB activation among the UMSCC lines (30).…”

Section: Limited Inhibitory Effects Of Hdis In Umscc Cells With Basalmentioning

confidence: 99%

“…30,31). Five micrograms of nuclear protein were incubated for 30 min at 21jC with biotinylated NF-nB probe.…”

Section: Inhibitors and Antibodiesmentioning

confidence: 99%

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Nuclear factor-κB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101

Duan

Friedman

Nottingham

et al. 2007

Molecular Cancer Therapeutics

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Histone deacetylase inhibitors (HDI) can inhibit proliferation and enhance apoptosis in a wide range of malignancies. However, HDIs show relatively modest activity in head and neck squamous cell carcinomas (HNSCC), in which we have shown the activation of nuclear factor-KB (NF-KB; NF-KB1/RelA or p50/p65), a transcription factor that promotes expression of proliferative and antiapoptotic genes. In this study, we examined if HDIs enhance activation of NF-KB and target genes and if genetic or pharmacologic inhibition of NF-KB can sensitize HNSCC to HDIs. Limited activity of classic HDIs trichostatin A and sodium butyrate was associated with enhanced activation of NF-KB reporter activity in a panel of six HNSCC cell lines. HDIs enhanced NF-KB p50/p65 DNA binding and acetylation of the RelA p65 subunit. Transfection of small interfering RNAs targeting p65 strongly inhibited NF-KB expression and activation, induced cell cycle arrest and cell death, and further sensitized HNSCC cells when combined with HDIs. The p65 small interfering RNA inhibited HDI-enhanced expression of several NF-KB -inducible genes implicated in oncogenesis of HNSCC, such as p21, cyclin D1, and BCL-XL. Bortezomib, an inhibitor of proteasome-dependent NF-KB activation, also increased sensitization to trichostatin A, sodium butyrate, and a novel HDI, PXD101, in vitro, and to the antitumor effects of PXD101 in bortezomib-resistant UMSCC-11A xenografts. However, gastrointestinal toxicity, weight loss, and mortality of the combination were dose limiting and required parenteral fluid administration. We conclude that HDI-enhanced NF-KB activation is one of the major mechanisms of resistance of HNSCC to HDIs.

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Section: Limited Inhibitory Effects Of Hdis In Umscc Cells With Basalmentioning

confidence: 69%

Section: Limited Inhibitory Effects Of Hdis In Umscc Cells With Basalmentioning

confidence: 99%

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Nuclear factor-κB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101

Duan

Friedman

Nottingham

et al. 2007

Molecular Cancer Therapeutics

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“…44 Similarly, for patients with high-grade dysplasia and squamous cell carcinoma of the tonsil, NFκB was associated with worse prognosis in terms of high recurrence and poor survival. 24 NFκB was an independent predictor for both overall survival and disease-free survival and was also associated with chemoradiation resistance in patients with esophageal cancer. 26,45 Lessard et al reported that all NFκB subunits were expressed in prostate tissues and nuclear localization of RelB (a subunit of NFκB) correlated with patient's Gleason scores.…”

Section: Introductionmentioning

confidence: 99%

“…First, NFκB has been related to cell transformation. 21 Second, NFκB is constitutively active in tissues of many cancers [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] (Table 2). Third, activation of inflammatory pathway is mediated through NFκB in response to lifestyle-related factors such as tobacco, stress, dietary agents, obesity, alcohol, infectious agents, irradiation and environmental stimuli, which account for as much as 95% of all cancers.…”

Section: Introductionmentioning

confidence: 99%

Targeting the inflammatory pathways to enhance chemotherapy of cancer

Zhu

Zhong²,

Zhang³

2011

Cancer Biology & Therapy

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Nuclear factor‐κB (nf‐κB) is frequently expressed in lung cancer and preneoplastic lesions

Tang¹,

Liu²,

Shishodia³

et al. 2006

Cancer

185

136

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BACKGROUND. Nuclear factor‐κB (NF‐κB), a key transcription factor thought to play a major role in carcinogenesis, regulates many important signaling pathways involved in tumor promotion. Although NF‐κB can be activated in lung cancer cell lines by tobacco exposure, there have been no studies of the expression of NF‐κB in lung cancer pathogenesis. METHODS. The immunohistochemical expression of NF‐κB p65 was investigated in 394 lung cancers (370 nonsmall cell lung carcinomas [NSCLC]; and 24 small cell lung carcinomas [SCLC]) and 269 lung normal epithelium and preneoplastic lesions, including hyperplasias, squamous metaplasias, dysplasias, and atypical adenomatous hyperplasias. RESULTS. High levels of nuclear immunohistochemical expression of NF‐κB p65 were detected in the lung cancers, with significantly higher levels in SCLCs compared with NSCLCs (P<.0001). In adenocarcinomas the NF‐κB p65 expression level was significantly higher in advanced TNM stages (III‐IV) than in earlier stages (I‐II) (P<.0001), and when NF‐κB p65 is dichotomized using 50% as the cutoff point (high vs low), a higher NF‐κB p65 expression level was detected in tumors having either K‐RAS (P = .02) or EGFR (P = .009) mutations compared with wildtype tumors. A relatively high level of nuclear NF‐κB p65 expression was detected in normal and mildly abnormal epithelium, and a progression with increasing histology severity was detected in preneoplastic lesions. CONCLUSIONS. NF‐κB p65 nuclear expression is an early and frequent phenomenon in the pathogenesis of lung cancer. The findings indicate that NF‐κB activation plays an important role in lung cancer pathogenesis and is a suitable target for the development of new lung cancer therapies and chemoprevention strategies. Cancer 2006. © 2006 American Cancer Society.

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Overexpression of phosphorylated nuclear factor-kappa B in tonsillar squamous cell carcinoma and high-grade dysplasia is associated with poor prognosis

Cited by 53 publications

References 30 publications

Nuclear factor-κB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101

Nuclear factor-κB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101

Targeting the inflammatory pathways to enhance chemotherapy of cancer

Nuclear factor‐κB (nf‐κB) is frequently expressed in lung cancer and preneoplastic lesions

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