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

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). The pres...

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Autores principales: Fan, Yali, Wang, Jiandong, Fang, Ziwei, Pierce, Stuart R., West, Lindsay, Staley, Allison, Tucker, Katherine, Yin, Yajie, Sun, Wenchuan, Kong, Weimin, Prabhu, Varun, Allen, Joshua E., Zhou, Chunxiao, Bae-Jump, Victoria L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970020/
https://www.ncbi.nlm.nih.gov/pubmed/35372029
http://dx.doi.org/10.3389/fonc.2022.789450
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author Fan, Yali
Wang, Jiandong
Fang, Ziwei
Pierce, Stuart R.
West, Lindsay
Staley, Allison
Tucker, Katherine
Yin, Yajie
Sun, Wenchuan
Kong, Weimin
Prabhu, Varun
Allen, Joshua E.
Zhou, Chunxiao
Bae-Jump, Victoria L.
author_facet Fan, Yali
Wang, Jiandong
Fang, Ziwei
Pierce, Stuart R.
West, Lindsay
Staley, Allison
Tucker, Katherine
Yin, Yajie
Sun, Wenchuan
Kong, Weimin
Prabhu, Varun
Allen, Joshua E.
Zhou, Chunxiao
Bae-Jump, Victoria L.
author_sort Fan, Yali
collection PubMed
description 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). The present study was to explore the anti-tumor potential effect of ONC201 in ovarian cancer cell lines and in a transgenic mouse model of high grade serous ovarian cancer under obese (high fat diet) and lean (low fat diet) conditions. 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. These results suggest that ONC201 may be a promising therapeutic agent to be explored in future clinical trials in high-grade serous ovarian cancer.
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spelling pubmed-89700202022-04-01 Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer Fan, Yali Wang, Jiandong Fang, Ziwei Pierce, Stuart R. West, Lindsay Staley, Allison Tucker, Katherine Yin, Yajie Sun, Wenchuan Kong, Weimin Prabhu, Varun Allen, Joshua E. Zhou, Chunxiao Bae-Jump, Victoria L. Front Oncol Oncology 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). The present study was to explore the anti-tumor potential effect of ONC201 in ovarian cancer cell lines and in a transgenic mouse model of high grade serous ovarian cancer under obese (high fat diet) and lean (low fat diet) conditions. 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. These results suggest that ONC201 may be a promising therapeutic agent to be explored in future clinical trials in high-grade serous ovarian cancer. Frontiers Media S.A. 2022-03-17 /pmc/articles/PMC8970020/ /pubmed/35372029 http://dx.doi.org/10.3389/fonc.2022.789450 Text en Copyright © 2022 Fan, Wang, Fang, Pierce, West, Staley, Tucker, Yin, Sun, Kong, Prabhu, Allen, Zhou and Bae-Jump https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Fan, Yali
Wang, Jiandong
Fang, Ziwei
Pierce, Stuart R.
West, Lindsay
Staley, Allison
Tucker, Katherine
Yin, Yajie
Sun, Wenchuan
Kong, Weimin
Prabhu, Varun
Allen, Joshua E.
Zhou, Chunxiao
Bae-Jump, Victoria L.
Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer
title Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer
title_full Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer
title_fullStr Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer
title_full_unstemmed Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer
title_short Anti-Tumor and Anti-Invasive Effects of ONC201 on Ovarian Cancer Cells and a Transgenic Mouse Model of Serous Ovarian Cancer
title_sort anti-tumor and anti-invasive effects of onc201 on ovarian cancer cells and a transgenic mouse model of serous ovarian cancer
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970020/
https://www.ncbi.nlm.nih.gov/pubmed/35372029
http://dx.doi.org/10.3389/fonc.2022.789450
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