Inflammation and Nitrosative Stress Effects in Ovarian and Prostate Pathology and Carcinogenesis

Burke, Amy J.; Garrido, Pablo; Johnson, Carol; Sullivan, Frank; Glynn, Sharon A.

doi:10.1089/ars.2017.7004

Cited by 23 publications

(15 citation statements)

References 99 publications

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“…3 were confirmed by measuring NO-derived NO 2 -/NO 3 -(NO x ) via the Griess assay. As shown in Fig.…”

Section: Jq1 Inhibition Of Inos Expression -mentioning

confidence: 89%

“…Most established malignant tumors exist under moderate inflammatory conditions, which foster tumor cell survival, proliferation, and metastatic expansion (1)(2)(3). Low level reactive oxygen species (ROS) as well as nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS/NOS2) play important roles in many of these processes (3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

“…Low level reactive oxygen species (ROS) as well as nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS/NOS2) play important roles in many of these processes (3)(4)(5)(6). There is now compelling evidence that endogenous iNOS/NO not only supports growth and progression of many tumors, but also plays a key role in pro-tumor immunosuppression (7,8) as well as resistance to chemotherapeutic and radiotherapeutic interventions (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Fahey

Stancill

Smith

et al. 2018

Journal of Biological Chemistry

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Endogenous nitric oxide (NO) generated by inducible NO synthase (iNOS) promotes glioblastoma cell proliferation and invasion, and also plays a key role in glioblastoma resistance to chemotherapy and radiotherapy. Non-ionizing photodynamic therapy (PDT) has anti-tumor advantages over conventional glioblastoma therapies. Our previous studies revealed that glioblastoma U87 cells upregulate iNOS after a photodynamic challenge and that resulting NO not only increased resistance to apoptosis, but rendered surviving cells more proliferative and invasive. These findings were largely based on the effects of inhibiting iNOS activity and scavenging NO. Demonstrating now that iNOS expression in photostressed U87 cells is mediated by NF-κB, we hypothesized that (i) recognition of acetylated lysine (acK) on NF-κB p65/Rel A by bromodomain and extra-terminal (BET) protein Brd4 is crucial, and (ii) by suppressing iNOS expression, a BET inhibitor (JQ1) would attenuate the negative effects of photostress. The following evidence was obtained: (i) Like iNOS, Brd4 protein and p65-acK levels increased several fold in photostressed cells; (ii) JQ1 at minimally toxic concentrations had no effect on Brd4 or p65-acK upregulation after PDT, but strongly suppressed iNOS, survivin, and Bcl-xL upregulation, along with the growth and invasion spurt of PDTsurviving cells; (iii) JQ1 inhibition of NO production in photostressed cells closely paralleled that of growth/invasion inhibition; (iv) At 1% the concentration of iNOS inhibitor 1400W, JQ1 reduced post-PDT cell aggressiveness to a far greater extent. This is the first evidence for BET inhibitor targeting of iNOS expression in cancer cells and how such targeting can markedly improve therapeutic efficacy.

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“…3 were confirmed by measuring NO-derived NO 2 -/NO 3 -(NO x ) via the Griess assay. As shown in Fig.…”

Section: Jq1 Inhibition Of Inos Expression -mentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Fahey

Stancill

Smith

et al. 2018

Journal of Biological Chemistry

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show abstract

“…We investigated the prognosis significance of the upregulated and druggable genes. Excluding those genes with no clinical relevance, and those which have already been associated with PCa, such as Ctsb, Gpx2, Idh1, and Nos2 [60][61][62][63][64][65][66], we selected the antioxidant enzyme Srxn1 that had a strong correlation with patient outcome and has no previous related functional studies in PCa.…”

Section: Oxidative Stress Response Genes Are Deregulated Duringmentioning

confidence: 99%

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

Barquilha

Santos

Monção

et al. 2020

Oxidative Medicine and Cellular Longevity

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The incidence of prostate cancer (PCa) is increasing, and it is currently the second most frequent cause of death by cancer in men. Despite advancements in cancer therapies, new therapeutic approaches are still needed for treatment-refractory advanced metastatic PCa. Cross-species analysis presents a robust strategy for the discovery of new potential therapeutic targets. This strategy involves the integration of genomic data from genetically engineered mouse models (GEMMs) and human PCa datasets. Considering the role of antioxidant pathways in tumor initiation and progression, we searched oxidative stress-related genes for a potential therapeutic target for PCa. First, we analyzed RNA-sequencing data from Pb-Cre4; Ptenf/f mice and discovered an increase in sulfiredoxin (Srxn1) mRNA expression in high-grade prostatic intraepithelial neoplasia (PIN), well-differentiated adenocarcinoma (medium-stage tumors), and poor-differentiated adenocarcinoma (advanced-stage prostate tumors). The increase of SRXN1 protein expression was confirmed by immunohistochemistry in mouse prostate tumor paraffin samples. Analyses of human databases and prostate tissue microarrays demonstrated that SRXN1 is overexpressed in a subset of high-grade prostate tumors and correlates with aggressive PCa with worse prognosis and decreased survival. Analyses in vitro showed that SRXN1 expression is also higher in most PCa cell lines compared to normal cell lines. Furthermore, siRNA-mediated downregulation of SRXN1 led to decreased viability of PCa cells LNCaP. In conclusion, we identified the antioxidant enzyme SRXN1 as a potential therapeutic target for PCa. Our results suggest that the use of specific SRXN1 inhibitors may be an effective strategy for the adjuvant treatment of castration-resistant PCa with SRXN1 overexpression.

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“…To assess whether TSNet could help to recover tumor specific biological activities that cannot be detected by mixNet, Figure 5b shows the degree of the top 10 mostly connected genes in TSNet networks which were poorly connected in mixNet. These genes include the tumor suppressor HIC1 ( Zheng et al , 2012 ), the voltage-gated calcium gene CACNA1I ( Phan et al , 2017 ), the lymphocyte-specific member of the tumor necrosis factor TNFRSF13B ( Block et al , 2014 ) and NOS2, a gene involved in antitumoral activities ( Burke et al , 2017 ). All these genes have been demonstrated to play an important role in cancer ( Block et al , 2014 ; Burke et al , 2017 ; Phan et al , 2017 ; Zheng et al , 2012 ).…”

Section: Tcga Ovarian Cancer Datamentioning

confidence: 99%

A new method for constructing tumor specific gene co-expression networks based on samples with tumor purity heterogeneity

et al. 2018

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MotivationTumor tissue samples often contain an unknown fraction of stromal cells. This problem is widely known as tumor purity heterogeneity (TPH) was recently recognized as a severe issue in omics studies. Specifically, if TPH is ignored when inferring co-expression networks, edges are likely to be estimated among genes with mean shift between non-tumor- and tumor cells rather than among gene pairs interacting with each other in tumor cells. To address this issue, we propose Tumor Specific Net (TSNet), a new method which constructs tumor-cell specific gene/protein co-expression networks based on gene/protein expression profiles of tumor tissues. TSNet treats the observed expression profile as a mixture of expressions from different cell types and explicitly models tumor purity percentage in each tumor sample.ResultsUsing extensive synthetic data experiments, we demonstrate that TSNet outperforms a standard graphical model which does not account for TPH. We then apply TSNet to estimate tumor specific gene co-expression networks based on TCGA ovarian cancer RNAseq data. We identify novel co-expression modules and hub structure specific to tumor cells.Availability and implementationR codes can be found at https://github.com/petraf01/TSNet.Supplementary information Supplementary data are available at Bioinformatics online.

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Inflammation and Nitrosative Stress Effects in Ovarian and Prostate Pathology and Carcinogenesis

Abstract: NOS2 and NO present new targets for the treatment of ovarian and prostate tumors. Furthermore, understanding NO-related tumor biology in these cancers presents a new means for improved patient stratification to the appropriate treatment regimen. Antioxid. Redox Signal. 26, 1078-1090.

Cited by 23 publications

References 99 publications

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer

A new method for constructing tumor specific gene co-expression networks based on samples with tumor purity heterogeneity

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