Deregulation of IKBKE Is Associated with Tumor Progression, Poor Prognosis, and Cisplatin Resistance in Ovarian Cancer

Guo, Jianping; Shu, Shaokun; He, Lili; Lee, Yi-Chun; Kruk, Patricia A.; Grénman, Seija; Nicosia, Santo V.; Mor, Gil; Schell, Michael J.; Coppola, Domenico; Cheng, Jin Q.

doi:10.2353/ajpath.2009.080767

Cited by 80 publications

(76 citation statements)

References 35 publications

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“…A similar inhibitory effect on cell proliferation was also observed following IKKε knockdown in HeLa cells and ovarian cancer cells (9,11). In agreement with these findings, we found that targeted knockdown of IKKε significantly suppresses glioma cell proliferation.…”

Section: Discussionsupporting

confidence: 89%

“…Our study revealed that elevated levels of IKKε are more frequently observed in high grade tumors, suggesting that alterations in IKKε expression are an early event in the development of some gliomas. A similar result was shown for IKKε expression in ovarian cancer progression (11). Further studies with more clinical samples are required to substantiate this observation.…”

Section: Discussionsupporting

confidence: 81%

“…Abnormal upregulation of NF-κB activity by IKKε was presumed to be an essential step for cell transformation (10). Guo et al showed that IKKε is overexpressed in a significant proportion of ovarian carcinomas (63/95), and elevated IKKε levels served as a marker for poor prognosis (11). IKKε is also reported to promote prostate cancer progression, by inducing secretion of IL-6, which may act as a positive growth factor in prostate cancer (12).…”

Section: Introductionmentioning

confidence: 99%

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Silencing of IKKε using siRNA inhibits proliferation and invasion of glioma cells in vitro and in vivo

Li¹,

Chen

Zhang³

et al. 2012

Int J Oncol

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Abstract. Recent studies implicated IKKε in the pathogenesis of many human cancers by promoting cell proliferation, increasing tumor angiogenesis and metastasis, and generating resistance to cell apoptosis. However, whether IKKε can influence the invasive ability and proliferation of glioma cells remains largely unknown. In this study, we showed that overexpression of IKKε is positively correlated to glioma pathological grade, suggesting that IKKε plays a role in tumor progression, rather than tumor initiation. Targeted knockdown of IKKε in human glioma cells using siRNA, was associated with inhibition of cell growth, cell cycle arrest and decreased cell invasion; however, notable apoptosis was not observed. Furthermore, we demonstrated that transposition of NF-κB p65 resulted in the alteration of these phenotypes. Tumor growth was attenuated in established subcutaneous gliomas in nude mice treated with IKKε siRNA in vivo. Collectively, our results suggest that deregulation of IKKε plays a pivotal role in the uncontrolled proliferation and malignant invasion of glioma cells in vitro and in vivo by targeting NF-κB. Silencing of IKKε using synthetic siRNAs may offer a novel therapeutic strategy for the treatment of glioma.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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Silencing of IKKε using siRNA inhibits proliferation and invasion of glioma cells in vitro and in vivo

Li¹,

Chen

Zhang³

et al. 2012

Int J Oncol

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“…IKK-ε was recently mapped as a new oncogene and was found to be overexpressed in prostate, ovarian, and breast cancer [20,21,36]. Interestingly, IKK-ε can replace a PI3K activity to inhibit cell-cycle arrest and apoptosis [20] processes associated with FOXO3 activity [16,37].…”

Section: Discussionmentioning

confidence: 99%

FOXO3 as a new IKK‐ε‐controlled check‐point of regulation of IFN‐β expression

et al. 2012

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Cell survival transcription factor FOXO3 has been recently implicated in moderating proinflammatory cytokine production by dendritic cells (DCs), but the molecular mechanisms are unclear. It was suggested that FOXO3 could antagonize NF-κB activity, while IKK-β was demonstrated to inactivate FOXO3, suggesting a cross-talk between the two pathways. Therefore, FOXO3 activity must be tightly regulated to allow for an appropriate inflammatory response. Here, we show that in human monocyte-derived DCs (MDDCs), FOXO3 is able to antagonize signaling intermediates downstream of the Toll-like receptor (TLR) 4, such as NF-κB and interferon regulatory factors (IRFs), resulting in inhibition of interferon (IFN)-β expression.We also demonstrate that the activity of FOXO3 itself is regulated by IKK-ε, a kinase involved in IFN-β production, which phosphorylates and inactivates FOXO3 in response to TLR4 agonists. Thus, we identify FOXO3 as a new IKK-ε-controlled check-point of IRF activation and regulation of IFN-β expression, providing new insight into the role of FOXO3 in immune response control.Keywords: Activation-induced cell death r Cell volume regulation r T-cell response r Taurine transporter Supporting Information available online IntroductionThe FOXO transcription factors (FOXO1, FOXO3, FOXO4, and FOXO6) are involved in a wide range of cellular processes including cell-cycle arrest, apoptosis, oxidative stress detoxification, and cellular homeostasis [1][2][3]. Given their importance in such critical cellular functions, their activity is tightly regulated by posttranslational modifications, mainly via the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway [4]. In response to growth factors or cytokines, FOXO proteins are phosphorylated by AKT Correspondence: Dr. Lionel Luron e-mail: luron@ciml.univ-mrs.fr at three conserved serine/threonine residues (Thr 32 , Ser 253 , and Ser 315 of FOXO3) resulting in the protein inactivation via nuclear exclusion and subsequent degradation [5,6].More recently, FOXO factors have been shown to play a role in immunity and inflammation [7][8][9][10][11]. In addition to their critical role in homeostasis of immune-relevant cells including B and T cells [7][8][9], FOXOs are associated with inflammatory diseases [12,13]. Moreover, FOXO3 was identified as a key factor in regulation of the innate immune response [10]. In FOXO3-deficient mice, production of major proinflammatory cytokines IL-6 and TNF-α by dendritic cells (DCs) is increased in response to viral infection, resulting in a greater expansion of T-cell population [10]. Expression of proinflammatory cytokines as well as type I interferons (IFNs) in response to viral and microbial stimuli is regulated by a number of key transcription factors, including NF-κB and [20,21]. Interestingly, its overexpression in a breast cancer model system could functionally replace PI3K constitutive activation and prevent cell-cycle arrest and apoptosis [20], processes often mediated by FOXO3 target genes, such as Cyclin D, p27/KIP1, FasL, bim...

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“…3 Recent studies have shown that IKBKE was overexpressed in breast cancer, 4 glioma, 5,6 ovarian cancer, 7 non-small cell lung cancer 8,9 and renal clear cell carcinoma. 10 IKBKE expression was also closely related to the pathological grade of the cancer, 6,7,9 chemoresistance 7,8 and induced malignant transformation. 4,9 Li et al 6 have demonstrated that the knockdown of IKBKE inhibits proliferation, migration and invasion in vitro and suppresses glioblastoma tumourigenesis in vivo.…”

Section: Introductionmentioning

confidence: 99%

IKBKE promotes glioblastoma progression by establishing the regulatory feedback loop of IKBKE/YAP1/miR-Let-7b/i

et al. 2017

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Recently, we have demonstrated that IKBKE (inhibitor of nuclear factor kappa-B kinase subunit epsilon) is overexpressed in human glioblastoma and that inhibition of IKBKE remarkably suppresses the proliferative and invasive behaviour of glioblastoma cells. However, the specific pathogenic molecular mechanism remains to be elucidated. In this study, we verified that IKBKE promotes YAP1 expression via posttranslational modification and accelerates YAP1 translocation to the nucleus for the development of glioblastoma. We then determined that YAP1 negatively regulates miR-let-7b/i by overexpressing and silencing YAP1 expression. In addition, miR-let-7b/i feedback decreases the expression of IKBKE and YAP1 and suppresses the transportation of YAP1 located in the nucleus. Therefore, the regulatory feedback circuit of IKBKE↑→YAP1↑→miR-let-7b/i↓→IKBKE↑ dictates glioblastoma progression. Thus, we propose that blocking the circuit may be a new therapeutic strategy for the treatment of glioblastoma.

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Deregulation of IKBKE Is Associated with Tumor Progression, Poor Prognosis, and Cisplatin Resistance in Ovarian Cancer

Cited by 80 publications

References 35 publications

Silencing of IKKε using siRNA inhibits proliferation and invasion of glioma cells in vitro and in vivo

Silencing of IKKε using siRNA inhibits proliferation and invasion of glioma cells in vitro and in vivo

FOXO3 as a new IKK‐ε‐controlled check‐point of regulation of IFN‐β expression

IKBKE promotes glioblastoma progression by establishing the regulatory feedback loop of IKBKE/YAP1/miR-Let-7b/i

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