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Domatinostat Targets the FOXM1–Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents

The deregulation of the FOXM1 transcription factor is a key molecular alteration in ovarian cancer, contributing to the development and progression of ovarian cancer via activation of the target genes. As such, FOXM1 is a highly attractive therapeutic target in the treatment of ovarian cancer, but t...

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Autores principales: Nakagawa-Saito, Yurika, Mitobe, Yuta, Suzuki, Shuhei, Togashi, Keita, Sugai, Asuka, Kitanaka, Chifumi, Okada, Masashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341571/
https://www.ncbi.nlm.nih.gov/pubmed/37445993
http://dx.doi.org/10.3390/ijms241310817
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author Nakagawa-Saito, Yurika
Mitobe, Yuta
Suzuki, Shuhei
Togashi, Keita
Sugai, Asuka
Kitanaka, Chifumi
Okada, Masashi
author_facet Nakagawa-Saito, Yurika
Mitobe, Yuta
Suzuki, Shuhei
Togashi, Keita
Sugai, Asuka
Kitanaka, Chifumi
Okada, Masashi
author_sort Nakagawa-Saito, Yurika
collection PubMed
description The deregulation of the FOXM1 transcription factor is a key molecular alteration in ovarian cancer, contributing to the development and progression of ovarian cancer via activation of the target genes. As such, FOXM1 is a highly attractive therapeutic target in the treatment of ovarian cancer, but there has been no clinically tested FOXM1 inhibitor to date. We investigated in this study the effects of domatinostat, a class I-selective HDAC inhibitor currently in the clinical stage of development as a cancer therapeutic, on the expression of FOXM1 and viability of ovarian cancer cells. Cell viability, as well as protein and mRNA expression of FOXM1 and its transcriptional target survivin, was examined after domatinostat treatment of TOV21G and SKOV3 ovarian cancer cell lines in the absence or presence of cisplatin and paclitaxel. The effect of FOXM1 knockdown on survivin expression and those of genetic and pharmacological inhibition of survivin alone or in combination with the chemotherapeutic agents on cell viability were also examined. Domatinostat reduced the protein and mRNA expression of FOXM1 and survivin and also the viability of ovarian cancer cells alone and in combination with cisplatin or paclitaxel at clinically relevant concentrations. Knockdown experiments showed survivin expression was dependent on FOXM1 in ovarian cancer cells. Survivin inhibition was sufficient to reduce the viability of ovarian cancer cells alone and in combination with the chemotherapeutic agents. Our findings suggest that domatinostat, which effectively targets the FOXM1–survivin axis required for the viability of ovarian cancer cells, is a promising option for the treatment of ovarian cancer.
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spelling pubmed-103415712023-07-14 Domatinostat Targets the FOXM1–Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents Nakagawa-Saito, Yurika Mitobe, Yuta Suzuki, Shuhei Togashi, Keita Sugai, Asuka Kitanaka, Chifumi Okada, Masashi Int J Mol Sci Article The deregulation of the FOXM1 transcription factor is a key molecular alteration in ovarian cancer, contributing to the development and progression of ovarian cancer via activation of the target genes. As such, FOXM1 is a highly attractive therapeutic target in the treatment of ovarian cancer, but there has been no clinically tested FOXM1 inhibitor to date. We investigated in this study the effects of domatinostat, a class I-selective HDAC inhibitor currently in the clinical stage of development as a cancer therapeutic, on the expression of FOXM1 and viability of ovarian cancer cells. Cell viability, as well as protein and mRNA expression of FOXM1 and its transcriptional target survivin, was examined after domatinostat treatment of TOV21G and SKOV3 ovarian cancer cell lines in the absence or presence of cisplatin and paclitaxel. The effect of FOXM1 knockdown on survivin expression and those of genetic and pharmacological inhibition of survivin alone or in combination with the chemotherapeutic agents on cell viability were also examined. Domatinostat reduced the protein and mRNA expression of FOXM1 and survivin and also the viability of ovarian cancer cells alone and in combination with cisplatin or paclitaxel at clinically relevant concentrations. Knockdown experiments showed survivin expression was dependent on FOXM1 in ovarian cancer cells. Survivin inhibition was sufficient to reduce the viability of ovarian cancer cells alone and in combination with the chemotherapeutic agents. Our findings suggest that domatinostat, which effectively targets the FOXM1–survivin axis required for the viability of ovarian cancer cells, is a promising option for the treatment of ovarian cancer. MDPI 2023-06-28 /pmc/articles/PMC10341571/ /pubmed/37445993 http://dx.doi.org/10.3390/ijms241310817 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nakagawa-Saito, Yurika
Mitobe, Yuta
Suzuki, Shuhei
Togashi, Keita
Sugai, Asuka
Kitanaka, Chifumi
Okada, Masashi
Domatinostat Targets the FOXM1–Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents
title Domatinostat Targets the FOXM1–Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents
title_full Domatinostat Targets the FOXM1–Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents
title_fullStr Domatinostat Targets the FOXM1–Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents
title_full_unstemmed Domatinostat Targets the FOXM1–Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents
title_short Domatinostat Targets the FOXM1–Survivin Axis to Reduce the Viability of Ovarian Cancer Cells Alone and in Combination with Chemotherapeutic Agents
title_sort domatinostat targets the foxm1–survivin axis to reduce the viability of ovarian cancer cells alone and in combination with chemotherapeutic agents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341571/
https://www.ncbi.nlm.nih.gov/pubmed/37445993
http://dx.doi.org/10.3390/ijms241310817
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