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

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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The effect of celecoxib on tumor growth in ovarian cancer cells and a genetically engineered mouse model of serous ovarian cancer

Oncotarget ◽

10.18632/oncotarget.8659 ◽

2016 ◽

Vol 7 (26) ◽

pp. 39582-39594 ◽

Cited By ~ 13

Author(s):

Anuj Suri ◽

Xiugui Sheng ◽

Kevin M. Schuler ◽

Yan Zhong ◽

Xiaoyun Han ◽

...

Keyword(s):

Ovarian Cancer ◽

Mouse Model ◽

Tumor Growth ◽

Cancer Cells ◽

Genetically Engineered ◽

Ovarian Cancer Cells ◽

Serous Ovarian Cancer ◽

Genetically Engineered Mouse Model

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Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer

Oncotarget ◽

10.18632/oncotarget.22012 ◽

2017 ◽

Vol 8 (59) ◽

pp. 100113-100127 ◽

Cited By ~ 11

Author(s):

Amanda L. Jackson ◽

Wenchuan Sun ◽

Joshua Kilgore ◽

Hui Guo ◽

Ziwei Fang ◽

...

Keyword(s):

Ovarian Cancer ◽

Mouse Model ◽

Cancer Cells ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Serous Ovarian Cancer ◽

Orthotopic Mouse Model

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Faculty Opinions recommendation of 17beta-estradiol accelerates tumor onset and decreases survival in a transgenic mouse model of ovarian cancer.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2753961.2417060 ◽

2010 ◽

Author(s):

Carlos Telleria

Keyword(s):

Ovarian Cancer ◽

Mouse Model ◽

Transgenic Mouse ◽

Transgenic Mouse Model ◽

Tumor Onset

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

Biomolecules ◽

10.3390/biom11111711 ◽

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.

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Abstract 2897: The metastatic potential of high-grade serous ovarian cancer cells along disease progression

10.1158/1538-7445.am2021-2897 ◽

2021 ◽

Author(s):

Sabrina J. Ritch ◽

Alicia A. Goyeneche ◽

Abu S. Noman ◽

Carlos M. Telleria

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Disease Progression ◽

Metastatic Potential ◽

Ovarian Cancer Cells ◽

High Grade ◽

Serous Ovarian Cancer

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Wnt5A and TGFβ1 Converges through YAP1 Activity and Integrin Alpha v Up-Regulation Promoting Epithelial to Mesenchymal Transition in Ovarian Cancer Cells and Mesothelial Cell Activation

Cells ◽

10.3390/cells11020237 ◽

2022 ◽

Vol 11 (2) ◽

pp. 237

Author(s):

Zeinab Dehghani-Ghobadi ◽

Shahrzad Sheikh Hasani ◽

Ehsan Arefian ◽

Ghamartaj Hossein

Keyword(s):

Ovarian Cancer ◽

Cell Migration ◽

Epithelial Ovarian Cancer ◽

Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Migration And Invasion ◽

Ovarian Cancer Cells ◽

Serous Ovarian Cancer ◽

Mesenchymal Transition ◽

Nuclear Shuttling

In this paper, we investigate whether Wnt5A is associated with the TGF-β1/Smad2/3 and Hippo-YAP1/TAZ-TEAD pathways, implicated in epithelial to mesenchymal transition (EMT) in epithelial ovarian cancer. We used 3D and 2D cultures of human epithelial ovarian cancer cell lines SKOV-3, OVCAR-3, CAOV-4, and different subtypes of human serous ovarian cancer compared to normal ovary specimens. Wnt5A showed a positive correlation with TAZ and TGFβ1 in high- and low-grade serous ovarian cancer specimens compared to borderline serous and normal ovaries. Silencing Wnt5A by siRNAs significantly decreased Smad2/3 activation and YAP1 expression and nuclear shuttling in ovarian cancer (OvCa) cells. Furthermore, Wnt5A was required for TGFβ1-induced cell migration and invasion. In addition, inhibition of YAP1 transcriptional activity by Verteporfin (VP) altered OvCa cell migration and invasion through decreased Wnt5A expression and inhibition of Smad2/3 activation, which was reverted in the presence of exogenous Wnt5A. We found that the activation of TGFβ1 and YAP1 nuclear shuttling was promoted by Wnt5A-induced integrin alpha v. Lastly, Wnt5A was implicated in activating human primary omental mesothelial cells and subsequent invasion of ovarian cancer cells. Together, we propose that Wnt5A could be a critical mediator of EMT-associated pathways.

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