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Mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the Akt/FOXO3 pathway

The outcome of chemotherapy for osteosarcoma have improved during the past decade and more patients have access to combination chemotherapy, but there has been no significant clinical progress in the patient survival rate. Recently, forkhead-box O3 (FOXO3) was identified as a pivotal transcription f...

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Autores principales: Park, See-Hyoung, Lee, Jongsung, Kang, Mi-Ae, Jang, Kyu Yun, Kim, Jung Ryul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004704/
https://www.ncbi.nlm.nih.gov/pubmed/29928344
http://dx.doi.org/10.3892/ol.2018.8547
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author Park, See-Hyoung
Lee, Jongsung
Kang, Mi-Ae
Jang, Kyu Yun
Kim, Jung Ryul
author_facet Park, See-Hyoung
Lee, Jongsung
Kang, Mi-Ae
Jang, Kyu Yun
Kim, Jung Ryul
author_sort Park, See-Hyoung
collection PubMed
description The outcome of chemotherapy for osteosarcoma have improved during the past decade and more patients have access to combination chemotherapy, but there has been no significant clinical progress in the patient survival rate. Recently, forkhead-box O3 (FOXO3) was identified as a pivotal transcription factor responsible for the transcriptional regulation of genes associated with suppression of cancer. The purpose of the present study was to screen small chemicals activating FOXO3 and elucidate their underlying mechanism. Using a drug discovery platform based on the phosphorylation status of FOXO3 in osteosarcoma cells, mitoxantrone (MTZ), a type of DNA-damaging agent, was selected as a possible FOXO3 activator from the food and drug administration-approved drug library. MTZ treatments significantly inhibited the phosphorylation level of Akt-pS473 and caused nuclear localization of FOXO3 in osteosarcoma cells. MTZ treatment inhibited proliferation in osteosarcoma cells in vitro, whereas silencing FOXO3 potently attenuates MTZ-mediated apoptosis in osteosarcoma cells. Taken together, the results indicated that MTZ induces apoptosis in osteosarcoma cells through an Akt/FOXO3-dependent mechanism.
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spelling pubmed-60047042018-06-20 Mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the Akt/FOXO3 pathway Park, See-Hyoung Lee, Jongsung Kang, Mi-Ae Jang, Kyu Yun Kim, Jung Ryul Oncol Lett Articles The outcome of chemotherapy for osteosarcoma have improved during the past decade and more patients have access to combination chemotherapy, but there has been no significant clinical progress in the patient survival rate. Recently, forkhead-box O3 (FOXO3) was identified as a pivotal transcription factor responsible for the transcriptional regulation of genes associated with suppression of cancer. The purpose of the present study was to screen small chemicals activating FOXO3 and elucidate their underlying mechanism. Using a drug discovery platform based on the phosphorylation status of FOXO3 in osteosarcoma cells, mitoxantrone (MTZ), a type of DNA-damaging agent, was selected as a possible FOXO3 activator from the food and drug administration-approved drug library. MTZ treatments significantly inhibited the phosphorylation level of Akt-pS473 and caused nuclear localization of FOXO3 in osteosarcoma cells. MTZ treatment inhibited proliferation in osteosarcoma cells in vitro, whereas silencing FOXO3 potently attenuates MTZ-mediated apoptosis in osteosarcoma cells. Taken together, the results indicated that MTZ induces apoptosis in osteosarcoma cells through an Akt/FOXO3-dependent mechanism. D.A. Spandidos 2018-06 2018-04-20 /pmc/articles/PMC6004704/ /pubmed/29928344 http://dx.doi.org/10.3892/ol.2018.8547 Text en Copyright: © Park et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Park, See-Hyoung
Lee, Jongsung
Kang, Mi-Ae
Jang, Kyu Yun
Kim, Jung Ryul
Mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the Akt/FOXO3 pathway
title Mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the Akt/FOXO3 pathway
title_full Mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the Akt/FOXO3 pathway
title_fullStr Mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the Akt/FOXO3 pathway
title_full_unstemmed Mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the Akt/FOXO3 pathway
title_short Mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the Akt/FOXO3 pathway
title_sort mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the akt/foxo3 pathway
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004704/
https://www.ncbi.nlm.nih.gov/pubmed/29928344
http://dx.doi.org/10.3892/ol.2018.8547
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