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Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol’s Anti-Tumor Angiogenesis Effect

Celastrol, an active triterpenoid extracted from one of the most famous traditional Chinese medicines (TCMs), Tripterygium wilfordii Hook.f., is a novel anti-cancer drug with significant anti-angiogenesis activity. However, the exact molecular mechanisms underlying its anti-tumor angiogenesis effect...

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Autores principales: Li, Gaofu, Zhou, Lei, Deng, Huifang, Huang, Congshu, Wang, Ningning, Yue, Lanxin, Zhang, Pengfei, Zhou, Yongqiang, Zhou, Wei, Gao, Yue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9866574/
https://www.ncbi.nlm.nih.gov/pubmed/36678677
http://dx.doi.org/10.3390/pharmaceutics15010048
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author Li, Gaofu
Zhou, Lei
Deng, Huifang
Huang, Congshu
Wang, Ningning
Yue, Lanxin
Zhang, Pengfei
Zhou, Yongqiang
Zhou, Wei
Gao, Yue
author_facet Li, Gaofu
Zhou, Lei
Deng, Huifang
Huang, Congshu
Wang, Ningning
Yue, Lanxin
Zhang, Pengfei
Zhou, Yongqiang
Zhou, Wei
Gao, Yue
author_sort Li, Gaofu
collection PubMed
description Celastrol, an active triterpenoid extracted from one of the most famous traditional Chinese medicines (TCMs), Tripterygium wilfordii Hook.f., is a novel anti-cancer drug with significant anti-angiogenesis activity. However, the exact molecular mechanisms underlying its anti-tumor angiogenesis effect remain unclear. The process of angiogenesis needs lots of energy supply, which mostly derives from mitochondria, the “energy factory” in our body. This study shows that celastrol exerts visible suppression on tumor growth and angiogenesis in a cell-derived xenograft (CDX). Likewise, it reduced the tube formation and migration of human umbilical vein endothelial cells (HUVECs), suppressed the energy metabolism of mitochondria in the Seahorse XF Mito Stress Test, and triggered mitochondrial fragmentation and NF-κB activation. Mechanically, celastrol downregulated the expression of mitochondrial-sharping protein optic atrophy protein 1 (OPA1), which was further estimated by the OPA1 knockdown model of HUVECs. Specifically, celastrol directly suppressed OPA1 at the mRNA level by inhibiting the phosphorylation of STAT3, and stattic (STAT3 inhibitor) showed the same effects on OPA1 suppression and anti-angiogenesis activity. Overall, this study indicates that celastrol inhibits tumor angiogenesis by suppressing mitochondrial function and morphology via the STAT3/OPA1/P65 pathway and provides new insight for mitochondrion-targeted cancer therapy.
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spelling pubmed-98665742023-01-22 Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol’s Anti-Tumor Angiogenesis Effect Li, Gaofu Zhou, Lei Deng, Huifang Huang, Congshu Wang, Ningning Yue, Lanxin Zhang, Pengfei Zhou, Yongqiang Zhou, Wei Gao, Yue Pharmaceutics Article Celastrol, an active triterpenoid extracted from one of the most famous traditional Chinese medicines (TCMs), Tripterygium wilfordii Hook.f., is a novel anti-cancer drug with significant anti-angiogenesis activity. However, the exact molecular mechanisms underlying its anti-tumor angiogenesis effect remain unclear. The process of angiogenesis needs lots of energy supply, which mostly derives from mitochondria, the “energy factory” in our body. This study shows that celastrol exerts visible suppression on tumor growth and angiogenesis in a cell-derived xenograft (CDX). Likewise, it reduced the tube formation and migration of human umbilical vein endothelial cells (HUVECs), suppressed the energy metabolism of mitochondria in the Seahorse XF Mito Stress Test, and triggered mitochondrial fragmentation and NF-κB activation. Mechanically, celastrol downregulated the expression of mitochondrial-sharping protein optic atrophy protein 1 (OPA1), which was further estimated by the OPA1 knockdown model of HUVECs. Specifically, celastrol directly suppressed OPA1 at the mRNA level by inhibiting the phosphorylation of STAT3, and stattic (STAT3 inhibitor) showed the same effects on OPA1 suppression and anti-angiogenesis activity. Overall, this study indicates that celastrol inhibits tumor angiogenesis by suppressing mitochondrial function and morphology via the STAT3/OPA1/P65 pathway and provides new insight for mitochondrion-targeted cancer therapy. MDPI 2022-12-23 /pmc/articles/PMC9866574/ /pubmed/36678677 http://dx.doi.org/10.3390/pharmaceutics15010048 Text en © 2022 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
Li, Gaofu
Zhou, Lei
Deng, Huifang
Huang, Congshu
Wang, Ningning
Yue, Lanxin
Zhang, Pengfei
Zhou, Yongqiang
Zhou, Wei
Gao, Yue
Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol’s Anti-Tumor Angiogenesis Effect
title Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol’s Anti-Tumor Angiogenesis Effect
title_full Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol’s Anti-Tumor Angiogenesis Effect
title_fullStr Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol’s Anti-Tumor Angiogenesis Effect
title_full_unstemmed Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol’s Anti-Tumor Angiogenesis Effect
title_short Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol’s Anti-Tumor Angiogenesis Effect
title_sort targeting opa1-mediated mitochondrial fusion contributed to celastrol’s anti-tumor angiogenesis effect
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9866574/
https://www.ncbi.nlm.nih.gov/pubmed/36678677
http://dx.doi.org/10.3390/pharmaceutics15010048
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