scholarly journals Proteomic Analysis Reveals Low-Dose PARP Inhibitor-Induced Differential Protein Expression in BRCA1-Mutated High-Grade Serous Ovarian Cancer Cells

2021 ◽  
Author(s):  
Jesenia M. Perez ◽  
Carly A. I. Twigg ◽  
Weihua Guan ◽  
Stefani N. Thomas
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Proteomic Analysis ◽  
Low Dose ◽  
Parp Inhibitor ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Differential Protein Expression ◽  
Differential Protein

scholarly journals Epigenetic Therapy Augments Classic Chemotherapy in Suppressing the Growth of 3D High-Grade Serous Ovarian Cancer Spheroids over an Extended Period of Time

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1711
Author(s):  
Michelle Bilbao ◽  
Chelsea Katz ◽  
Stephanie L. Kass ◽  
Devon Smith ◽  
Krystal Hunter ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
3D Culture ◽  
Extended Period ◽  
Recurrent Ovarian Cancer ◽  
Epigenetic Therapy ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Cancer Spheroids

Recurrent high-grade serous ovarian cancer (HGSC) is clinically very challenging and prematurely shortens patients’ lives. Recurrent ovarian cancer is characterized by high tumor heterogeneity; therefore, it is susceptible to epigenetic therapy in classic 2D tissue culture and rodent models. Unfortunately, this success has not translated well into clinical trials. Utilizing a 3D spheroid model over a period of weeks, we were able to compare the efficacy of classic chemotherapy and epigenetic therapy on recurrent ovarian cancer cells. Unexpectedly, in our model, a single dose of paclitaxel alone caused the exponential growth of recurrent high-grade serous epithelial ovarian cancer over a period of weeks. In contrast, this effect is not only opposite under treatment with panobinostat, but panobinostat reverses the repopulation of cancer cells following paclitaxel treatment. In our model, we also demonstrate differences in the drug-treatment sensitivity of classic chemotherapy and epigenetic therapy. Moreover, 3D-derived ovarian cancer cells demonstrate induced proliferation, migration, invasion, cancer colony formation and chemoresistance properties after just a single exposure to classic chemotherapy. To the best of our knowledge, this is the first evidence demonstrating a critical contrast between short and prolonged post-treatment outcomes following classic chemotherapy and epigenetic therapy in recurrent high-grade serous ovarian cancer in 3D culture.

scholarly journals Prolactin signaling drives tumorigenesis in human high grade serous ovarian cancer cells and in a spontaneous fallopian tube derived model

2018 ◽  
Vol 433 ◽  
pp. 221-231 ◽  
Author(s):  
Subbulakshmi Karthikeyan ◽  
Angela Russo ◽  
Matthew Dean ◽  
Daniel D. Lantvit ◽  
Michael Endsley ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Fallopian Tube ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Prolactin Signaling

Abstract P205: Novel 1,1-diarylethylene compounds degrade FOXM1 and selectively and potently reduce survival of high-grade serous ovarian cancer cells

2021 ◽  
Author(s):  
Cassie Liu ◽  
Catalina Muñoz-Trujillo ◽  
John A. Katzenellenbogen ◽  
Benita S. Katzenellenbogen ◽  
Adam R. Karpf
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer

scholarly journals MYC Targeted Rad50 Drives Progression of High-Grade Serous Ovarian Cancer via NF-κB Activation

2020 ◽  
Author(s):  
Yinuo Li ◽  
Shourong Wang ◽  
Peng Li ◽  
Yingwei Li ◽  
Yao Liu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Ectopic Expression ◽  
Strand Break ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Mice Model ◽  
Interacting Protein ◽  
Mrn Complex

Abstract BackgroundRad50 is a component of MRN complex, which consists of Mre11-Rad50-Nbs1. The MRN complex participates in DNA double-strand break repair and DNA-damage checkpoint activation. We sought to investigate the clinical and functional significance of Rad50 in high-grade serous ovarian cancer. MethodsChromatin immunoprecipitation and luciferase assays were performed to evaluate the regulatory roles of MYC on Rad50 expression. Association between Rad50 expression and clinical outcome in HGSOCs was evaluated by Kaplan-Meier analysis. Invasion, clonogenic assay and xenograft mice model were conducted to determine to functional role of Rad50 in ovarian cancer. Protein immunoprecipitation and immunofluorescence were used to explore the underlying mechanisms. ResultsMYC proto-oncogene transcriptionally activated Rad50 expression in high-grade serous ovarian cancer. Next, we provided evidences that Rad50 was frequently upregulated in HGSOCs and enhanced Rad50 expression inversely correlated with patient’s survival. In addition, ectopic expression of Rad50 promoted proliferation/invasion and induced EMT of ovarian cancer cells, whereas knockdown of Rad50 led to decreased aggressive behaviors. Mechanistic investigations revealed that Rad50 induced aggressiveness in HGSOC via activation NF-κB signaling pathway. Moreover, we identified CARD9 as an interacting protein of Rad50 in ovarian cancer cells and activation of NF-κB pathway by Rad50 is CARD9 dependent. ConclusionsOur findings provide evidence that MYC targeted Rad50 exhibits oncogenic property via NF-κB activation in high-grade serous ovarian cancer.

scholarly journals A Unique Pattern of Mesothelial-Mesenchymal Transition Induced in the Normal Peritoneal Mesothelium by High-Grade Serous Ovarian Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 662 ◽  
Author(s):  
Martyna Pakuła ◽  
Paweł Uruski ◽  
Arkadiusz Niklas ◽  
Aldona Woźniak ◽  
Dariusz Szpurek ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Specific Pattern ◽  
Laboratory Animals ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Mesenchymal Transition

The study was designed to establish whether high aggressiveness of high-grade serous ovarian cancer cells (HGSOCs), which display rapid growth, advanced stage at diagnosis and the highest mortality among all epithelial ovarian cancer histotypes, may be linked with a specific pattern of mesothelial-mesenchymal transition (MMT) elicited by these cells in normal peritoneal mesothelial cells (PMCs). Experiments were performed on primary PMCs, stable and primary ovarian cancer cells, tumors from patients with ovarian cancer, and laboratory animals. Results of in vitro and in vivo tests showed that MMT triggered by HGSOCs (primary cells and OVCAR-3 line) is far more pronounced than the process evoked by cells representing less aggressive ovarian cancer histotypes (A2780, SKOV-3). Mechanistically, HGSOCs induce MMT via Smad 2/3, ILK, TGF-β1, HGF, and IGF-1, whereas A2780 and SKOV-3 cells via exclusively Smad 2/3 and HGF. The conditioned medium from PMCs undergoing MMT promoted the progression of cancer cells and the effects exerted by the cells triggered to undergo MMT by the HGSOCs were significantly stronger than those related to the activity of their less aggressive counterparts. Our findings indicate that MMT in PMCs provoked by HGSOCs is stronger, proceeds via different mechanisms and has more procancerous characteristics than MMT provoked by less aggressive cancer histotypes, which may at least partly explain high aggressiveness of HGSOCs.

scholarly journals Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer

2021 ◽  
Author(s):  
Yali Fan ◽  
Jiandong Wang ◽  
Ziwei Fang ◽  
Stuart R Pierce ◽  
Lindsay West ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Cellular Stress ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Mesenchymal Transition

Abstract Background: ONC201 is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as activation of mitochondrial caseinolytic protease P (ClpP).Methods: Our objective was to evaluate the effect of the ONC201 on (1) proliferation, cellular stress, apoptosis and invasion in human serous ovarian cancer (OC) cell lines, and (2) inhibition of tumor growth in a genetically engineered mouse model of high grade serous OC (K18-gT121+/-;p53fl/fl;Brca1fl/fl; KpB) under obese (high fat diet) and lean (low fat diet) conditions. Results: ONC201 significantly suppressed cell proliferation, induced arrest in G1 phase, and increased cellular stress and apoptosis, accompanied by dual inhibition of the AKT/mTOR/S6 and MAPK pathways in OC cells. ONC201 also resulted in inhibition of adhesion and invasion via epithelial–mesenchymal transition and reduction of VEGF expression. Pre-treatment with the anti-oxidant, N-acetylcysteine (NAC), reversed the ONC201-induced oxidative stress response, and prevented ONC201-reduced VEGF and cell invasion by regulating epithelial–mesenchymal transition protein expression. Knockdown of ClpP in ovarian cancer cells reduced ONC201 mediated the anti-tumor activity and cellular stress. Diet-induced obesity accelerated ovarian tumor growth in the KpB mouse model. ONC201 significantly suppressed tumor growth, and decreased serum VEGF production in obese and lean mice, leading to a decrease in tumoral expression of Ki-67, VEGF and phosphorylation of p42/44 and S6 and an increase in ClpP and DRD5, as assessed by immunohistochemistry. Additionally, ONC201 exhibited greater anti-tumor efficacy in obese (75%) as compared to lean (65%) mice. InterpretationConclusions: These results suggest that ONC206 may be a promising therapeutic agent to be explored in future clinical trials in high grade serous OC.

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