The Biphasic Role of NF-κB in Progression and Chemoresistance of Ovarian Cancer

Abstract

Purpose 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. Experimental Design 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. Results 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. Conclusions 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.

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

“…NFKB1 functions as a biphasic regulator, either suppressing or enhancing the development of ovarian cancer. As a tumor suppressor in ovarian cancer cell lines, NFKB1 regulates MAPK, while in the aggressive chemoresistant isogenic variants of these lines it plays a role in apoptosis (46). In addition, PDCD4 enhances chemosensitivity of ovarian cancer cells by activating death receptor pathway in vitro and in vivo (47), and the loss of MLH1 mediated by methylation can lead to the cisplatin-resistance in ovarian cancer (48,49).…”

IKKβ Regulates VEGF Expression and Is a Potential Therapeutic Target for Ovarian Cancer as an Antiangiogenic Treatment

“…Kleinberg and colleagues reported that the nuclear localization of NF-kB/RelA (p65) is frequently expressed in advanced stage serous ovarian carcinomas, and is associated with poor PFS (15), while Annunziata and colleagues wrote that high expression of cytoplasmic NF-kB1 (p50) was associated with poor survival in patients with advanced-stage ovarian cancer (16). However, more recently, Yang and colleagues showed that the nuclear accumulation of p65 in epithelial ovarian carcinomas is significantly associated with a good response to chemotherapy and can predict longer OS of patients (17). For these reasons, we were encouraged to analyze whether NF-kB signaling regulates VEGF expression in ovarian cancer tissues as well as whether targeting this signaling can be an alternative option for the inhibition of VEGF expression, leading to a new antiangiogenic therapy.…”

Prognostication of Nf-Κb and P53 Expression in Different Stage and Grade of Ovarian Cancer.

“…Christina M at al demonstrates that role of NF-κB progression was correlated with advanced ovarian cancer [17]. Various study reported that NF-κB was a poor prognostic marker in ovarian cancer [18,19,20]. No correlation was found between NF-κB expression vs age at diagnosis.…”

“…In Indian scenario ovarian cancer is third leading side of cancer among female next to cervical and breast cancer [1,3]. Survival of ovarian cancer depends on various pathological and molecular factors [4,5,6,7]. But nothing has been proved conclusive to be the best for overall survival of ovarian cancer.…”

“…Histopathological parameters are type of carcinoma, tumor size, grade and lymph node metastasis. Several studies have reported that there are various prognostic markers in ovarian cancer [5,6,7].The nuclear factor-κB (NF-κB) family of genes are associated with cell proliferation, angiogenesis, metastasis, oncogenesis and survival of ovarian cancer [8,9]. Some studies demonstrated that the association between NF-κB and tumor progression commonly involved the p65 subunit [11][12][13].NF-κB regulates over 500 genes involved in cellular transformation, survival, proliferation, invasion, angiogenesis, metastasis, and inflammation.…”