Progesterone Prevents High-Grade Serous Ovarian Cancer by Inducing Necroptosis of p53-Defective Fallopian Tube Epithelial Cells

Wu, Na-Yi Yuan; Huang, Hsuan-Shun; Chao, Tung; Chou, Hsien Ming; Fang, Chao; Qin, Chong-Zhen; Lin, Chia-Ho; Chu, Tang–Yuan; Zhou, Hong

doi:10.1016/j.celrep.2017.02.049

Cited by 63 publications

(69 citation statements)

References 30 publications

(35 reference statements)

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“…It is possible that the earlier loss of ovarian function and decreased P4 levels further increase HGSOC risk. Consistent with this, Wu et al [16] recently showed that P4 signaling induces necroptosis and clearance of p53-mutated FTE cells. Transformed FTE cells with intact P4 signaling are therefore responsive to signals that induce necroptosis.…”

Section: Introductionsupporting

confidence: 55%

“…Wu et al showed that P4 signaling induces necroptosis and clearance of p53-mutated FTE cells [16]. However, given the changes in necroptosis signaling in HGSOC compared to FTE, particularly the drastic downregulation of PGR (Table 1 and Fig.…”

Section: Established Hgsoc Cells Maintain the Capacity To Activate Nementioning

confidence: 96%

“…P4 treatment commonly results in the upregulation of a wide array of genes including Tumor Necrosis Factor alpha (TNFα), a factor that can promote programmed cell death (PCD) mechanisms including apoptosis and necroptosis [16]. Necroptosis is induced by TNFα interaction with the TNFα receptor (TNFR) promoting multiple downstream events including the formation of a complex containing TRAF2, cIAP1, TRADD, and the serine/threonine kinase receptor-interacting protein 1 (RIPK1) [17].…”

Section: Introductionmentioning

confidence: 99%

“…Necroptosis is induced by TNFα interaction with the TNFα receptor (TNFR) promoting multiple downstream events including the formation of a complex containing TRAF2, cIAP1, TRADD, and the serine/threonine kinase receptor-interacting protein 1 (RIPK1) [17]. The formation of this complex can lead to cell death via apoptosis (caspase 8-dependent) or necroptosis (caspase 8-independent) [18], the latter resulting from mixed lineage kinase domain-like protein (MLKL) activation and subsequent mitochondrial dysfunction and ROS production [16]. While a complete mechanistic understanding behind RIPK1-dependent PCD remains unclear, it is hypothesized to depend on post-translational modifications.…”

Section: Introductionmentioning

confidence: 99%

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Eliciting OTUD3/RIPK-Dependent Necroptosis to Prevent Epithelial Ovarian Cancer

Johnson

Bales

Bitler

et al. 2020

Preprint

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Background: There is an urgent need for early prevention strategies against high grade serous ovarian carcinoma (HGSOC), the deadliest gynecologic malignancy. Transformed p53-null fallopian tube epithelium (FTE) cells are precursors of HGSOC that may be eliminated by inducing necroptosis, a programmed form of inflammatory cell death. Induction of necroptosis is dependent upon activation of receptor-interacting serine/threonine-protein kinases 1 and 3 (RIPK1/3). TNFα and progesterone (P4) effectively promote necroptosis. In this study, we explore the activation of necroptosis as an approach to inhibit HGSOC progression.Methods: Using gene ontology sets as a reference, we analyzed publicly available datasets of HGSOC to correlate the expression of necroptosis effectors to clinical outcomes. Using in vitro models of HGSOC we evaluated the effect of TNFα, P4, and α-eleostearic acid on necroptosis.In parallel, the necroptosis inhibitor Necrostatin-1 was used to confirm necroptosis-specific cell death.Results: Expression of the P4 receptor (PGR) was sharply reduced in a HGSOC cohort compared to normal, nonmalignant FTE. However, several genes involved in necroptosis signaling were elevated in HGSOC, including TNF and RIPK1. Increased expression of PGR, the necroptosis effectors TNF and RIPK1/3, as well as ovarian tumor domain-containing deubiquitinase 3 (OTUD3) were associated with higher overall survival in 484 HGSOC cases.HGSOC cells activated necroptosis in response to P4, TNFα, and α-eleostearic acid treatment, while P4 or TNFα treatment of HGSOC cells increased TNF, RIPK1, and OTUD3 expression.OTUD3 is a putative tumor suppressor that stabilizes PTEN and is hypothesized to be functionally similar to the necroptosis inducer, OTUD7B. shRNA knockdown of OTUD3 resulted in decreased PTEN protein and RIPK1 protein. Conclusions:We conclude that necroptosis activation may be a viable prevention strategy that leads to the elimination of transformed FTE "founder" cells and prevents HGSOC tumorigenesis.Our data indicate that HGSOC cells activate necroptosis in response to P4, TNFα, and αeleostearic acid, suggesting that established HGSOC cells may also be eliminated by activating necroptosis. # Log2 fold change of HGSOC (n=11) compared to FTE (n=24) * P-value corrected for false-discovery rate by Benjamini-Hochberg method

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Section: Introductionsupporting

confidence: 55%

Section: Established Hgsoc Cells Maintain the Capacity To Activate Nementioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Eliciting OTUD3/RIPK-Dependent Necroptosis to Prevent Epithelial Ovarian Cancer

Johnson

Bales

Bitler

et al. 2020

Preprint

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“…High-grade serous ovarian cancer (HGSOC), a type of extremely malignant type II tumour, accompanied by extensive early metastasis, causes most of the morbidity and mortality associated with ovarian carcinomas [7]. Both clinical observations and mechanistic research support the hypothesis that the distal end of the tube is the main origin of early HGSOC carcinogenesis [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a DNA Aptamer for Ovarian Cancer Clinical Tissue Recognition and in Vivo Imaging

Wang

Zhang

et al. 2018

Cell Physiol Biochem

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Backgrounds/Aims: Ovarian cancer is the most lethal gynaecologic malignancy and is difficult to detect early. The inefficient early diagnosis of ovarian cancer is the main contributor to its high mortality rate. Aptamers, as chemical antibodies, are single-stranded DNA or RNA oligonucleotides that target cells or molecules with high affinity. Methods: Binding ability of R13 was measured by flow cytometry analysis. Stability of R13 was tested in blood serum of an ovarian cancer patient. Internalization of R13 was verified by confocal microscope imaging. 80 cases ovarian cancer tissues, 10 cases normal ovary tissues in a microarray and 6 fallopian tube tissues were prepared for this study. R13’s target ability was further confirmed in vivo tumor models in NOD/SCID mice. Results: In this study, we found aptamer R13 bound to ovarian cancer cells with dissociation constants in the nanomolar range. Moreover, these results were further confirmed by tissue imaging. Next we demonstrated that the targets of R13 are membrane proteins and that its internalization occurs in a caveolae-mediated and clathrin-mediated manner. The target function of R13 was determined by imaging A2780 tumours in mouse models. Conclusion: These findings suggest that R13 is a promising novel tool to diagnose and deliver drugs to treat ovarian cancer.

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Necroptosis‐related regulatory pattern and scoring system for predicting therapeutic efficacy and prognosis in ovarian cancer

Lai,

Guo,

et al. 2023

Cancer Reports

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BackgroundOvarian cancer is difficult to treat and is, therefore, associated with a high fatality rate. Although targeted therapy and immunotherapy have been successfully used clinically to improve the diagnosis and treatment of ovarian cancer, most tumors become drug resistant, and patients experience relapse, meaning that the overall survival rate remains low.AimsThere is currently a lack of effective biomarkers for predicting the prognosis and/or outcomes of patients with ovarian cancer. Therefore, we used published transcriptomic data derived from a large ovarian cancer sample set to establish a molecular subtyping model of the core genes involved in necroptosis in ovarian cancer.Methods and ResultsClustering analysis and differential gene expression analyses were performed to establish the genomic subtypes related to necroptosis and to explore the patterns of regulatory gene expression related to necroptosis in ovarian cancer. A necroptosis scoring system (NSS) was established using principal component analysis according to different regulatory patterns of necroptosis. In addition, this study revealed important biological processes with essential roles in the regulation of ovarian tumorigenesis, including external encapsulating structure organization, leukocyte migration, oxidative phosphorylation, and focal adhesion. Patients with high NSS scores had unique immunophenotypes, such as more abundant M2 macrophages, monocytes, CD4+ memory T cells, and regulatory T cells. Immune checkpoint CD274 had a greater expression in patients with high NSS values.ConclusionThis NSS could be used as an independent predictor of prognosis to determine the sensitivity of ovarian cancer to various small‐molecule inhibitors, immune checkpoint inhibitors, and platinum‐based chemotherapy drugs.

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Progesterone Prevents High-Grade Serous Ovarian Cancer by Inducing Necroptosis of p53-Defective Fallopian Tube Epithelial Cells

Cited by 63 publications

References 30 publications

Eliciting OTUD3/RIPK-Dependent Necroptosis to Prevent Epithelial Ovarian Cancer

Eliciting OTUD3/RIPK-Dependent Necroptosis to Prevent Epithelial Ovarian Cancer

Characterization of a DNA Aptamer for Ovarian Cancer Clinical Tissue Recognition and in Vivo Imaging

Necroptosis‐related regulatory pattern and scoring system for predicting therapeutic efficacy and prognosis in ovarian cancer

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