scholarly journals Exploring New Molecular Targets in Advanced Ovarian Cancer: The Aryl Hydrocarbon Receptor (AhR) and Antitumor Benzothiazole Ligands as Potential Therapeutic Candidates

2019 ◽  
Author(s):  
Andrea I. Loaiza Perez ◽  
Tracey D. Bradshaw
Keyword(s):  
Ovarian Cancer ◽  
Aryl Hydrocarbon Receptor ◽  
Molecular Targets ◽  
Advanced Ovarian Cancer ◽  
Aryl Hydrocarbon ◽  
New Molecular Targets

scholarly journals Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 463 ◽  
Author(s):  
Wei-Min Chung ◽  
Yen-Ping Ho ◽  
Wei-Chun Chang ◽  
Yuan-Chang Dai ◽  
Lumin Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Androgen Receptor ◽  
Epithelial Ovarian Cancer ◽  
Aryl Hydrocarbon Receptor ◽  
Proximal Promoter ◽  
Luciferase Reporter ◽  
Aryl Hydrocarbon ◽  
Paclitaxel Treatment

Background: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the AR remains unclear. Methods: To elucidate AR-related paclitaxel sensitivity, co-IP, luciferase reporter assay and ChIP assay were performed to identify that AR direct-regulated ABCG2 expression under paclitaxel treatment. IHC staining by AR antibody presented higher AR expression in serous-type patients than other types. AR degradation enhancer (ASC-J9) was used to examine paclitaxel-associated and paclitaxel-resistant cytotoxicity in vitro and in vivo. Results: We found AR/aryl hydrocarbon receptor (AhR)-mediates ABCG2 expression and leads to a change in paclitaxel cytotoxicity/sensitivity in EOC serous subtype cell lines. Molecular mechanism study showed that paclitaxel activated AR transactivity and bound to alternative ARE in the ABCG2 proximal promoter region. To identify AR as a potential therapeutic target, the ASC-J9 was used to re-sensitize paclitaxel-resistant EOC tumors upon paclitaxel treatment in vitro and in vivo. Conclusion: The results demonstrated that activation of AR transactivity beyond the androgen-associated biological effect. This novel AR mechanism explains that degradation of AR is the most effective therapeutic strategy for treating AR-positive EOC serous subtype.

scholarly journals The effect of certain autophagy proteins (LC3b and Beclin) and apotosis (Casp8 and Bcl-2) on the clinical course of ovarian cancer

2021 ◽  
Vol 67 (4) ◽  
pp. 474-479
Author(s):  
Aliia Gafiullina ◽  
Zinaida Afanaseva ◽  
Karim Garipov ◽  
Zinaida Abramova
Keyword(s):  
Systematic Review ◽  
Ovarian Cancer ◽  
Drug Therapy ◽  
Molecular Mechanisms ◽  
Clinical Course ◽  
Molecular Targets ◽  
Cochrane Library ◽  
Search For Information ◽  
New Molecular Targets

Treatment of ovarian cancer remains an important problem in practical oncology due to the increase in morbidity and mortality from this disease. The aim is to summarize the available literature data on the molecular mechanisms of the participation of various proteins of autophagy and apoptosis in the development, progression, formation of chemoresistance and in the assessment of the prognosis of epithelial ovarian cancer. Materials and methods. The search for information was carried out in the materials of the databases Medline, Cochrane Library, Elibrary, NCBI, RSCI, instructions for the medical use of drugs, using keywords in the title. Used 39 articles to write this systematic review. Results. The review examines the molecular mechanisms of autophagy and apoptosis involved in the progression of ovarian cancer and in the formation of resistance to anticancer drug therapy. It has been shown that modulation of autophagy and apoptosis can change the effectiveness of drug treatment for this tumor. Conclusion. Considering the literature data on the ambiguous role of autophagy and apoptosis in the course of ovarian cancer and the formation of resistance to antitumor treatment, further study is required and the search for new molecular targets for their modulation is required.

scholarly journals Indoleamine 2,3-dioxygenase upregulates PD-1 expression on ovarian tumor infiltrating CD8+ T cells via kynurenine activation of the aryl hydrocarbon receptor

2021 ◽  
Author(s):  
Adaobi Amobi-McCloud ◽  
Ravikumar Muthuswamy ◽  
Sebastiano Battaglia ◽  
Han Yu ◽  
Tao Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Tumor Immunity ◽  
Metabolic Pathways ◽  
Ovarian Tumor ◽  
Chromatin Accessibility ◽  
Indoleamine 2,3 Dioxygenase ◽  
Aryl Hydrocarbon ◽  
Ido1 Expression

AbstractThe immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO1) and the PD-1/PD-L1 axis are potent mechanisms that impede effective anti-tumor immunity in ovarian cancer. However, whether the IDO pathway regulates PD-1 expression in T cells is currently unknown. Here we show that tumoral IDO1 expression led to profound changes in tryptophan, nicotinate/nicotinamide, and purine metabolic pathways in the ovarian tumor microenvironment, and to an increased frequency of PD-1+CD8+ tumor infiltrating T cells. We determined that activation of the aryl hydrocarbon receptor (AHR) by kynurenine induced PD-1 expression, and this effect was significantly abrogated by the AHR antagonist CH223191. Mechanistically, kynurenine alters chromatin accessibility in regulatory regions of T cell inhibitory receptors, allowing AHR to bind to consensus XRE motifs in the promoter region of PD-1. These results enable the design of strategies to target the IDO1 and AHR pathways for enhancing anti-tumor immunity in ovarian cancer.

scholarly journals IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Adaobi Amobi-McCloud ◽  
Ravikumar Muthuswamy ◽  
Sebastiano Battaglia ◽  
Han Yu ◽  
Tao Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Tumor Immunity ◽  
Metabolic Pathways ◽  
Ovarian Tumor ◽  
Receptor Activation ◽  
Chromatin Accessibility ◽  
Aryl Hydrocarbon ◽  
Ido1 Expression

The immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO1) and the PD-1/PD-L1 axis are potent mechanisms that impede effective anti-tumor immunity in ovarian cancer. However, whether the IDO pathway regulates PD-1 expression in T cells is currently unknown. Here we show that tumoral IDO1 expression led to profound changes in tryptophan, nicotinate/nicotinamide, and purine metabolic pathways in the ovarian tumor microenvironment, and to an increased frequency of PD-1+CD8+ tumor infiltrating T cells. We determined that activation of the aryl hydrocarbon receptor (AHR) by kynurenine induced PD-1 expression, and this effect was significantly abrogated by the AHR antagonist CH223191. Mechanistically, kynurenine alters chromatin accessibility in regulatory regions of T cell inhibitory receptors, allowing AHR to bind to consensus XRE motifs in the promoter region of PD-1. These results enable the design of strategies to target the IDO1 and AHR pathways for enhancing anti-tumor immunity in ovarian cancer.

scholarly journals Correlation of the Aryl Hydrocarbon Receptor with FSHR in Ovarian Cancer Patients

2019 ◽  
Vol 20 (12) ◽  
pp. 2862 ◽  
Author(s):  
Eileen Deuster ◽  
Doris Mayr ◽  
Anna Hester ◽  
Thomas Kolben ◽  
Christine Zeder-Göß ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Aryl Hydrocarbon Receptor ◽  
Cancer Patients ◽  
Functional Role ◽  
Clear Cell ◽  
Staining Intensity ◽  
Prognostic Impact ◽  
Histological Subtypes ◽  
Aryl Hydrocarbon ◽  
The Impact

Expression of the aryl hydrocarbon receptor (AhR) has been described in various tumor entities from different organs. However, its role in ovarian cancer has not been thoroughly investigated. We aimed to elucidate the prognostic impact of AhR, its correlation with the follicle-stimulating hormone receptor (FSHR), and their functional role in ovarian cancer. By immunohistochemistry, AhR staining was analyzed in a subset of 156 samples of ovarian cancer patients. AhR staining was assessed in the nucleus and the cytoplasm using the semi-quantitative immunoreactive score (IRS), and the scores were grouped into high- and low-level expression. AhR expression was detected in all histological subtypes, with clear cell ovarian cancer displaying the highest staining intensity. Low cytoplasmic expression of AhR was associated with longer overall survival (median 183.46 vs. 85.07 months; p = 0.021). We found a positive correlation between AhR and FSHR (p = 0.005). Ovarian cancer patients with high cytoplasmic AhR and concurrent FSHR expression had the worst outcome (median 69.72 vs. 43.32 months; p = 0.043). Consequently, low cytoplasmic AhR expression seems to be associated with improved survival in ovarian cancer patients. Our data suggest that AhR and FSHR levels correlate with each other, and their concurrent expression was observed in ovarian cancer patients with the worst outcome. Further investigation of the interaction of both receptors and their functional role might better predict the impact of endocrine therapy in ovarian cancer.

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