Article

The biphasic role of NF-kappaB in progression and chemoresistance of ovarian cancer.

Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.
Clinical Cancer Research (impact factor: 7.74). 02/2011; 17(8):2181-94. DOI:10.1158/1078-0432.CCR-10-3265 pp.2181-94
Source: PubMed

ABSTRACT NF-κB is a transcription factor known to promote tumorigenesis. However, NF-κB is also known to be proapoptotic and may potentially function as a tumor suppressor, although such a functional role has not been extensively investigated in human cancer.
A dominant-negative mutant of IκBα with mutations at S32A and S36A was used to inhibit the function of NF-κB in ovarian cancer cell lines. The transcription ability, tumorigenesis, apoptosis, and drug sensitivity were examined in derivative cell lines in comparison with parental cells. We also analyzed the association of nuclear expression of NF-κB p65 with patient survival in an ovarian cancer tissue array.
We show that NF-κB functions as a tumor suppressor in four ovarian cancer cell lines, but it functions as an oncogene in their aggressive chemoresistant isogenic variants. NF-κB can exert its proapoptotic or antiapoptotic effect by activating or repressing mitogen-activated protein kinase (MAPK) phosphorylation in parental or aggressive chemoresistant variant cell lines. We also show that the nuclear accumulation of p65 in epithelial cancer tissue is associated with a good response to chemotherapy and can predict longer overall survival for patients with ovarian cancer.
Our data provide strong evidence that NF-κB can function as a biphasic regulator, either suppressing or enhancing ovarian cancer growth through the regulation of MAPK and cellular apoptosis.

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    K M Ryan, M K Ernst, N R Rice, K H Vousden
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    ABSTRACT: The tumour suppressor p53 inhibits cell growth through activation of cell-cycle arrest and apoptosis, and most cancers have either mutation within the p53 gene or defects in the ability to induce p53. Activation or re-introduction of p53 induces apoptosis in many tumour cells and may provide effective cancer therapy. One of the key proteins that modulates the apoptotic response is NF-kappaB, a transcription factor that can protect or contribute to apoptosis. Here we show that induction of p53 causes an activation of NF-kappaB that correlates with the ability of p53 to induce apoptosis. Inhibition or loss of NF-kappaB activity abrogated p53-induced apoptosis, indicating that NF-kappaB is essential in p53-mediated cell death. Activation of NF-kappaB by p53 was distinct from that mediated by tumour-necrosis factor-alpha and involved MEK1 and the activation of pp90rsk. Inhibition of MEK1 blocked activation of NF-kappaB by p53 and completely abrogated p53-induced cell death. We conclude that inhibition of NF-kappaB in tumours that retain wild-type p53 may diminish, rather than augment, a therapeutic response.
    Nature 05/2000; 404(6780):892-7. · 36.28 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

aggressive chemoresistant isogenic variants
 
aggressive chemoresistant variant cell lines
 
biphasic regulator
 
cellular apoptosis
 
derivative cell lines
 
drug sensitivity
 
epithelial cancer tissue
 
good response
 
human cancer
 
NF-κB p65
 
nuclear accumulation
 
nuclear expression
 
ovarian cancer
 
ovarian cancer cell lines
 
ovarian cancer growth
 
ovarian cancer tissue array
 
parental cells
 
repressing mitogen-activated protein kinase
 
transcription factor
 
tumor suppressor