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PF-06409577 Activates AMPK Signaling and Inhibits Osteosarcoma Cell Growth
Osteosarcoma (OS) is a common primary bone malignancy. We here investigated the potential activity of PF-06409577, a novel, potent, and direct activator of AMP-activated protein kinase (AMPK), against human OS cells. In established (U2OS, MG-63, and SaOs-2 lines) and primary human OS cells, PF-06409...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316637/ https://www.ncbi.nlm.nih.gov/pubmed/34336655 http://dx.doi.org/10.3389/fonc.2021.659181 |
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author | Zhu, Yun-Rong Zhang, Xiang-Yang Wu, Qiu-Ping Yu, Cheng-Jian Liu, Yuan-Yuan Zhang, Yun-Qing |
author_facet | Zhu, Yun-Rong Zhang, Xiang-Yang Wu, Qiu-Ping Yu, Cheng-Jian Liu, Yuan-Yuan Zhang, Yun-Qing |
author_sort | Zhu, Yun-Rong |
collection | PubMed |
description | Osteosarcoma (OS) is a common primary bone malignancy. We here investigated the potential activity of PF-06409577, a novel, potent, and direct activator of AMP-activated protein kinase (AMPK), against human OS cells. In established (U2OS, MG-63, and SaOs-2 lines) and primary human OS cells, PF-06409577 inhibited cell viability and proliferation, while inducing cell apoptosis and cell cycle arrest. PF-06409577 induced AMPK activation, mTORC1 inhibition, autophagy induction, and downregulation of multiple receptor tyrosine kinase inOS cells. AMPK inactivation by AMPKα1 shRNA, CRISPR/Cas9 knockout, or dominant negative mutation (T172A) was able to abolish PF-06409577-induced activity in OS cells. In vivo, PF-06409577 oral administration at well-tolerated doses potently inhibited growth of U2OS cells and primary human OS cells in severe combined immunodeficient mice. AMPK activation, mTORC1 inhibition, autophagy induction, as well as RTK degradation and apoptosis activation were detected in PF-06409577-treated xenografts. In conclusion, activation of AMPK by PF-06409577 inhibits OS cell growth. |
format | Online Article Text |
id | pubmed-8316637 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83166372021-07-29 PF-06409577 Activates AMPK Signaling and Inhibits Osteosarcoma Cell Growth Zhu, Yun-Rong Zhang, Xiang-Yang Wu, Qiu-Ping Yu, Cheng-Jian Liu, Yuan-Yuan Zhang, Yun-Qing Front Oncol Oncology Osteosarcoma (OS) is a common primary bone malignancy. We here investigated the potential activity of PF-06409577, a novel, potent, and direct activator of AMP-activated protein kinase (AMPK), against human OS cells. In established (U2OS, MG-63, and SaOs-2 lines) and primary human OS cells, PF-06409577 inhibited cell viability and proliferation, while inducing cell apoptosis and cell cycle arrest. PF-06409577 induced AMPK activation, mTORC1 inhibition, autophagy induction, and downregulation of multiple receptor tyrosine kinase inOS cells. AMPK inactivation by AMPKα1 shRNA, CRISPR/Cas9 knockout, or dominant negative mutation (T172A) was able to abolish PF-06409577-induced activity in OS cells. In vivo, PF-06409577 oral administration at well-tolerated doses potently inhibited growth of U2OS cells and primary human OS cells in severe combined immunodeficient mice. AMPK activation, mTORC1 inhibition, autophagy induction, as well as RTK degradation and apoptosis activation were detected in PF-06409577-treated xenografts. In conclusion, activation of AMPK by PF-06409577 inhibits OS cell growth. Frontiers Media S.A. 2021-07-14 /pmc/articles/PMC8316637/ /pubmed/34336655 http://dx.doi.org/10.3389/fonc.2021.659181 Text en Copyright © 2021 Zhu, Zhang, Wu, Yu, Liu and Zhang 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 Zhu, Yun-Rong Zhang, Xiang-Yang Wu, Qiu-Ping Yu, Cheng-Jian Liu, Yuan-Yuan Zhang, Yun-Qing PF-06409577 Activates AMPK Signaling and Inhibits Osteosarcoma Cell Growth |
title | PF-06409577 Activates AMPK Signaling and Inhibits Osteosarcoma Cell Growth |
title_full | PF-06409577 Activates AMPK Signaling and Inhibits Osteosarcoma Cell Growth |
title_fullStr | PF-06409577 Activates AMPK Signaling and Inhibits Osteosarcoma Cell Growth |
title_full_unstemmed | PF-06409577 Activates AMPK Signaling and Inhibits Osteosarcoma Cell Growth |
title_short | PF-06409577 Activates AMPK Signaling and Inhibits Osteosarcoma Cell Growth |
title_sort | pf-06409577 activates ampk signaling and inhibits osteosarcoma cell growth |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316637/ https://www.ncbi.nlm.nih.gov/pubmed/34336655 http://dx.doi.org/10.3389/fonc.2021.659181 |
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