NF-κB is constitutively activated in high-grade squamous intraepithelial lesions and squamous cell carcinomas of the human uterine cervix

Nair, Asha S.; Manickam, Venkatraman; Maliekal, Tessy Thomas; Nair, Balaraman; Karunagaran, Devarajan

doi:10.1038/sj.onc.1206043

Cited by 142 publications

(122 citation statements)

References 52 publications

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“…These findings in prostate tumorigenesis are consistent with previous observations in other cancer types, such as gastric (Sasaki et al, 2001), uterine cervix (Nair et al, 2003), colorectal (Yu et al, 2003), breast (Biswas et al, 2004), and head and neck squamous cell cancers , showing that NF-kB activation occurs mainly in established cancer tissues rather than in normal or premalignant lesions. In the present study, NF-kB staining was not significantly linked to other known prognostic factors of biochemical relapse such as preoperative PSA levels, surgical margins or Gleason grade.…”

Section: Discussionsupporting

confidence: 92%

Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

et al. 2005

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Nuclear factor (NF)-kB/p65 regulates the transcription of a wide variety of genes involved in cell survival, invasion and metastasis. We characterised by immunohistochemistry the expression of NF-kB/p65 protein in six histologically normal prostate, 13 high-grade prostatic intraepithelial neoplasia (PIN) and 86 prostate adenocarcinoma specimens. Nuclear localisation of p65 was used as a measure of NF-kB active state. Nuclear localisation of NF-kB was only seen in scattered basal cells in normal prostate glands. Prostatic intraepithelial neoplasias exhibited diffuse and strong cytoplasmic staining but no nuclear staining. In prostate adenocarcinomas, cytoplasmic NF-kB was detected in 57 (66.3%) specimens, and nuclear NF-kB (activated) in 47 (54.7%). Nuclear and cytoplasmic NF-kB staining was not correlated (P ¼ 0.19). By univariate analysis, nuclear localisation of NF-kB was associated with biochemical relapse (P ¼ 0.0009; log-rank test) while cytoplasmic expression did not. On multivariate analysis, serum preoperative prostate specific antigen (P ¼ 0.02), Gleason score (P ¼ 0.03) and nuclear NF-kB (P ¼ 0.002) were independent predictors of biochemical relapse. These results provide novel evidence for NF-kB/p65 nuclear translocation in the transition from PIN to prostate cancer. Our findings also indicate that nuclear localisation of NF-kB is an independent prognostic factor of biochemical relapse in prostate cancer.

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Section: Discussionsupporting

confidence: 92%

Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

et al. 2005

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“…The cellular changes we observed in the cervical epithelium following 3-MC treatment closely resemble the progressive stages of human squamous cell carcinoma that constitute 80% of human cervical cancer. Nair et al (2003) have reported that there is an increased nuclear localization and DNA-binding activity of NF-kB as the grade of human cervical cancer progresses, which was also reflected in our 3-MC model, making it a suitable model for evaluating the synergistic effect of paclitaxel and curcumin in vivo. To validate the results obtained in the 3-MC model, we used the xenograft model using human cancer cell line HeLa, which has HPV oncogenes integrated within.…”

Section: Discussionmentioning

confidence: 91%

“…The nuclear expression of NF-kB might be considered as an indicator of malignant transformation and, interestingly, it is well demonstrated that NF-kB is constitutively activated during human cervical cancer progression (Nair et al, 2003). Reports also indicate that inhibition of NF-kB ameliorates the pathogenesis and overcomes therapeutic resistance (Ahn et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer

et al. 2011

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The microtubule-targeting antineoplastic agent, paclitaxel, is highly efficacious against a wide spectrum of human cancers. However, dose-limiting toxicity and development of drug resistance limit its clinical application. Development of novel strategies that overcome chemoresistance and sensitize cancer cells to paclitaxel can enhance the therapeutic effect of this drug. We have previously shown that curcumin, a natural polyphenol, enhances paclitaxelinduced cytotoxicity in vitro through downregulation of nuclear factor (NF)-jB and Akt pathways. This study was undertaken to determine whether this synergism exists in vivo and to elucidate the underlying molecular mechanisms. Mouse cervical multistage squamous cell carcinoma model using 3-methylcholanthrene (3-MC) and a xenograft model of human cervical cancer in nonobese diabetic severe combined immunodeficient (NOD-SCID) mice using HeLa cells were used to evaluate the synergism. We observed that the combined treatment of curcumin and paclitaxel induced a synergestic reduction in the tumor incidence as well as tumor volume of animals compared with the individual treatments of paclitaxel or curcumin, although curcumin alone could not induce any significant effect at the concentration used. The results suggest that a suboptimal concentration of curcumin augments the antitumor action of paclitaxel by downregulating the activation and downstream signaling of antiapoptotic factors and survival signals such as NF-jB, Akt and mitogen-activated protein kinases that have significant roles in proliferation, survival, angiogenesis and metastasis. This study revealed for the first time that 3-MC-induced tumorigenesis in mice is associated with a strong constitutive activation of NF-jB activity. Furthermore, we also observed that pre-exposure of carcinoma cells isolated from 3-MC-induced tumors to curcumin potentiates paclitaxel-induced apoptosis. Overall, the findings of this preclinical study provide a strong rationale for the validation of this combination through clinical trials. As curcumin could effectively downregulate all these survival signals induced by paclitaxel, we suggest it as a potent chemosensitizer to improve the therapeutic index of paclitaxel.

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“…Overall survival dependent on cytoplasmic (C and E) and nuclear (D and F) RelA overexpression for the whole study cohort (C and D) as well as for the subgroup of node-negative patients (E and F). Sweeney et al, 2004), endometrial (Pallares et al, 2004), hepatocellular (Tai et al, 2000) and oral (Nakayama et al, 2001) as well as cervical (Nair et al, 2003) carcinoma. Reports on RelA expression in pancreatic cancer are sparse.…”

Section: Discussionmentioning

confidence: 99%

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

et al. 2007

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Activation of nuclear factor-kB (NF-kB) signaling was observed in pancreatic adenocarcinoma cell lines and tumours. However, information on the expression of RelA/p65, the major transcription activating NF-kB subunit, in these carcinomas and possible correlations thereof with NF-kB activation and patient survival is not available. To provide this missing translational link, we analysed expression of RelA/p65 in 82 pancreatic adenocarcinomas by immunohistochemistry. Moreover, we measured activation of the NF-kB pathway in 11 tumours by quantitative PCR for NF-kB target genes. We observed strong cytoplasmic or nuclear expression of RelA/p65 in 42 and 37 carcinomas, respectively. High cytoplasmic and nuclear expression of RelA/p65 had negative prognostic impact with 2-year survival rates for patients without cytoplasmic or nuclear RelA/p65 positivity of 41 and 40% and rates for patients with strong cytoplasmic or nuclear RelA/p65 expression of 22 and 20%, respectively. High RelA/p65 expression was correlated to increased expression of NF-kB target genes. The observation that high expression of RelA/p65 is correlated to an activation of the NF-kB pathway and indicates poor patient survival identifies a patient subgroup that might particularly benefit from NF-kB-inhibiting agents in the treatment of pancreatic cancer. Based on our findings, this subgroup could be identified by applying simple immunohistochemical techniques.

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NF-κB is constitutively activated in high-grade squamous intraepithelial lesions and squamous cell carcinomas of the human uterine cervix

Cited by 142 publications

References 52 publications

Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

Molecular evidences for the chemosensitizing efficacy of liposomal curcumin in paclitaxel chemotherapy in mouse models of cervical cancer

High expression of RelA/p65 is associated with activation of nuclear factor-κB-dependent signaling in pancreatic cancer and marks a patient population with poor prognosis

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