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Expression of p52, a non-canonical NF-kappaB transcription factor, is associated with poor ovarian cancer prognosis.

ABSTRACT: Background:The canonical and non-canonical nuclear factor-kappaB (NF-?B) signaling pathways have key roles in cancer, but studies have previously evaluated only the association of canonical transcription factors and ovarian cancer survival. Although a number of in vitro and in vivo studies have demonstrated mechanisms by which non-canonical NF-?B signaling potentially contributes to ovarian cancer progression, a prognostic association has yet to be shown in the clinical context. Methods:We assayed p65 and p52 (major components of the canonical and non-canonical NF-?B pathways) by immunohistochemistry in epithelial ovarian tumor samples; nuclear and cytoplasmic staining were semi-quantified by H-scores and dichotomized at median values. Associations of p65 and p52 with progression-free survival (PFS) and overall survival (OS) were quantified by Hazard Ratios (HR) from proportional-hazards regression. Results:Among 196 cases, median p52 and p65 H-scores were higher in high-grade serous cancers. Multivariable regression models indicated that higher p52 was associated with higher hazards of disease progression (cytoplasmic HR: 1.54; nuclear HR: 1.67) and death (cytoplasmic HR: 1.53; nuclear HR: 1.49), while higher nuclear p65 was associated with only a higher hazard of disease progression (HR: 1.40) in unadjusted models. When cytoplasmic and nuclear staining were combined, p52 remained significantly associated with increased hazards of disease progression (HR: 1.91, p?=?0.004) and death (HR: 1.70, p?=?0.021), even after adjustment for p65 and in analyses among only high-grade serous tumors. Conclusions:This is the first study to demonstrate that p52, a major component of non-canonical NF-?B signaling, may be an independent prognostic factor for epithelial ovarian cancer, particularly high-grade serous ovarian cancer. Approaches to inhibit non-canonical NF-?B signaling should be explored as novel ovarian cancer therapies are needed.

SUBMITTER: Hufnagel DH

PROVIDER: S-EPMC7493985 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Expression of p52, a non-canonical NF-kappaB transcription factor, is associated with poor ovarian cancer prognosis.

Hufnagel Demetra H DH Wilson Andrew J AJ Saxon Jamie J Blackwell Timothy S TS Watkins Jaclyn J Khabele Dineo D Crispens Marta A MA Yull Fiona E FE Beeghly-Fadiel Alicia A

Biomarker research 20200915

<h4>Background</h4>The canonical and non-canonical nuclear factor-kappaB (NF-κB) signaling pathways have key roles in cancer, but studies have previously evaluated only the association of canonical transcription factors and ovarian cancer survival. Although a number of in vitro and in vivo studies have demonstrated mechanisms by which non-canonical NF-κB signaling potentially contributes to ovarian cancer progression, a prognostic association has yet to be shown in the clinical context.<h4>Metho ...[more]

PMID: 32974032

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Project description:The ability of the transcription factor NF-kappaB to upregulate anti-apoptotic proteins has been linked to the chemoresistance of solid tumors to standard chemotherapy. In contrast, recent studies have proposed that, in response to doxorubicin, NF-kappaB can be pro-apoptotic through repression of anti-apoptotic target genes. However, there is little evidence analyzing the outcome of NF-kappaB inhibition on the cytotoxicity of doxorubicin in studies describing pro-apoptotic NF-kappaB activity. In this study, we further characterize the activation of NF-kappaB in response to doxorubicin and evaluate its role in chemotherapy-induced cell death in sarcoma cells where NF-kappaB is reported to be pro-apoptotic. Doxorubicin treatment in U2OS cells induced canonical NF-kappaB activity as evidenced by increased nuclear accumulation of phosphorylated p65 at serine 536 and increased DNA-binding activity. Co-treatment with a small molecule IKKbeta inhibitor, Compound A, abrogated this response. RT-PCR evaluation of anti-apoptotic gene expression revealed that doxorubicin-induced transcription of cIAP2 was inhibited by Compound A, while doxorubicin-induced repression of other anti-apoptotic genes was unaffected by Compound A or siRNA to p65. Furthermore, the combination of doxorubicin and canonical NF-kappaB inhibition with Compound A or siRNA to p65 resulted in decreased cell viability measured by trypan blue staining and MTS assay and increased apoptosis measured by cleaved poly (ADP-ribose) polymerase and cleaved caspase 3 when compared to doxorubicin alone. Our results demonstrate that doxorubicin-induced canonical NF-kappaB activity associated with phosphorylated p65 is anti-apoptotic in its function and that doxorubicin-induced repression of anti-apoptotic genes occurs independent of p65. Therefore, combination therapies incorporating NF-kappaB inhibitors together with standard chemotherapies remains a viable method to improve the clinical outcomes in patients with advanced stage malignancies.

Dataset Information

Expression of p52, a non-canonical NF-kappaB transcription factor, is associated with poor ovarian cancer prognosis.

Publications

Expression of p52, a non-canonical NF-kappaB transcription factor, is associated with poor ovarian cancer prognosis.

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