IKK-ϵ Coordinates Invasion and Metastasis of Ovarian Cancer

Hsu, Sarah; Kim, Marianne; Hernandez, Lídia; Grajales, Valentina; Noonan, Anne; Anver, Miriam R.; Davidson, Ben; Annunziata, Christina M.

doi:10.1158/0008-5472.can-11-3993

Cited by 45 publications

(45 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Here we again demonstrate increased NFkB activity in TNBC cells in suspension as measured by an NFkB-promoter luciferase reporter, and this increase is not observed using a reporter containing a mutated binding site (Figure 5A). Interestingly, a recent global profiling study of ovarian cancer in vivo found that knockdown of Iκκ-epsilon, a positive regulator of NFkB activity, decreased expression of TDO2 and KYNU , suggesting NFκB regulation of these genes [36]; however, the regulatory mechanism was not directly tested.…”

Section: Resultsmentioning

confidence: 99%

A TDO2-AhR Signaling Axis Facilitates Anoikis Resistance and Metastasis in Triple-Negative Breast Cancer

et al. 2015

View full text Add to dashboard Cite

Anoikis is programmed death of epithelial cells triggered by detachment from a basement membrane or extracellular matrix, and anoikis resistance is a critical step in metastasis. Triple-negative breast cancers (TNBC) have a high rate of metastasis in the first 3 years following diagnosis, and although TNBC cell lines are more resistant to anoikis than estrogen receptor positive lines, little is known regarding pathways that support anoikis resistance. Gene expression and metabolomic profiling of TNBC cells in forced suspension culture revealed multiple genes in the kynurenine pathway of tryptophan catabolism upregulated by TNBC cells in suspension, including tryptophan 2,3-dioxygenase (TDO2). Increased production of kynurenine, a key metabolite of this pathway, by TNBC in suspension activated aryl hydrocarbon receptor (AhR) transcriptional activity. Pharmacological inhibition or knockdown of TDO2 decreased kynurenine production, increased anoikis sensitivity, and inhibited proliferation, migration, and invasion. Likewise, AhR inhibition or knockdown also decreased proliferation, migration, and anchorage-independent growth. Mining publically available data, TDO2 was found to be higher with increasing grade, higher in estrogen receptor negative than positive breast cancer, and associated with shorter overall survival. This study reveals a TDO2-AhR signaling axis activated by TNBC cells in suspension in an NF-κB dependent manner, and suggests TDO2 inhibition as a targeted therapy for TNBC. Indeed, pharmacological inhibition of TDO2 activity decreased lung colonization in a preclinical model of TNBC.

show abstract

Section: Resultsmentioning

confidence: 99%

A TDO2-AhR Signaling Axis Facilitates Anoikis Resistance and Metastasis in Triple-Negative Breast Cancer

et al. 2015

View full text Add to dashboard Cite

show abstract

“…[27] This pathway appears to play a crucial role in the process that links inflammation to cancer. [28, 29] Specifically, activation of NF-κB through inhibitor of κB kinase epsilon (IKKε) was shown to be associated with more aggressive behavior in ovarian cancer cell lines [30] and has been associated with aberrant cellular activities in endometriosis, a known risk factor for ovarian cancer. [31]…”

Section: Discussionmentioning

confidence: 99%

Pre-diagnostic serum levels of inflammation markers and risk of ovarian cancer in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial

Trabert

Pinto

Hartge

et al. 2014

Gynecologic Oncology

View full text Add to dashboard Cite

Objective Pro-inflammatory mechanisms may explain the increased ovarian cancer risk linked to more lifetime ovulations, endometriosis, and exposure to talc and asbestos, as well as decreased risk with non-steroidal antiinflammatory drugs. Limited data are available to estimate ovarian cancer risk associated with levels of circulating inflammatory markers. Methods We conducted a nested case-control study within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Pre-diagnostic serum levels of 46 inflammation-related biomarkers (11 with a priori hypotheses; 35 agnostic) were measured in 149 incident ovarian cancer cases and 149 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression and adjusted for identified covariates. Results Increased ovarian cancer risk was associated with elevated levels of C-reactive protein (CRP) [tertile (T)3 vs. T1: OR (95% CI) 2.04 (1.06-3.93), p-trend=0.03], interleukin (IL)-1α [detectable vs. undetectable: 2.23 (1.14-4.34)] and tumor necrosis factor alpha (TNF-α) [T3 vs. T1: 2.21 (1.06-4.63), p-trend=0.04] Elevated IL-8 was non-significantly associated with risk [T3 vs. T1: 1.86 (0.96-3.61), p-trend=0.05] In analyses restricted to serous ovarian cancer (n=83), the associations with CRP and IL-8 remained or strengthened [CRP T3 vs. T1: 3.96 (1.14-11.14), p-trend=0.008; IL-8 T3 vs. T1: 3.05 (1.09-8.51), p-trend=0.03]. Elevated levels of CRP and TNF-α remained positively associated with ovarian cancer risk in analysis restricted to specimens collected at least 5 years before diagnosis (n=56). Conclusion These results suggest that CRP, IL-1α, IL-8, and TNF-α are associated with increased risk of subsequently developing ovarian cancer.

show abstract

“…An inverse correlation between NF-κB (p50) and ovarian cancer patient's survival was observed in a clinical investigation; and inhibiting IKK-ε in ovarian cancer cells effectively reduced tumor progression [149, 150], suggesting NF-κB activation contributes to ovarian cancer development. Several miRNAs have been reported to regulate NF-κB activity via different pathways.…”

Section: Microrna In Regulation Of Nf-κb Signaling Circuits In Canmentioning

confidence: 99%

Therapeutic microRNAs targeting the NF-kappa B signaling circuits of cancers

Tong¹,

Yuan²,

Wu³

2015

Advanced Drug Delivery Reviews

View full text Add to dashboard Cite

MicroRNAs (miRNAs) not only directly regulate NF-κB expression, but also up- or down-regulate NF-κB activity via upstream and downstream signaling pathways of NF-κB. In many cancer cells, miRNA expressions are altered accompanied with an elevation of NF-κB, which often plays a role in promoting cancer development and progression as well as hindering the effectiveness of chemo and radiation therapies. Thus NF-κB-targeting miRNAs have been identified and characterized as potential therapeutics for cancer treatment and sensitizers of chemo and radiotherapies. However, due to cross-targeting and instability of miRNAs, some limitations of using miRNA as cancer therapeutics still exist. In this review, the mechanisms for miRNA-mediated alteration of NF-κB expression and activation in different types of cancers will be discussed. The results of therapeutic use of NF-κB-targeting miRNA for cancer treatment will be examined. Some limitations, challenges and potential strategies in future development of miRNA as cancer therapeutics are also assessed.

show abstract

IKK-ϵ Coordinates Invasion and Metastasis of Ovarian Cancer

Cited by 45 publications

References 25 publications

A TDO2-AhR Signaling Axis Facilitates Anoikis Resistance and Metastasis in Triple-Negative Breast Cancer

A TDO2-AhR Signaling Axis Facilitates Anoikis Resistance and Metastasis in Triple-Negative Breast Cancer

Pre-diagnostic serum levels of inflammation markers and risk of ovarian cancer in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial

Therapeutic microRNAs targeting the NF-kappa B signaling circuits of cancers

Contact Info

Product

Resources

About