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), <i>Tripterygium wilfordii</i> Hook.f., is a novel anti-cancer drug with significant anti-angiogenesis activity. However, the exact molecular mechanisms underlying its anti-tumor...
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MDPI AG
2022-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/1/48 |
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| author | Gaofu Li Lei Zhou Huifang Deng Congshu Huang Ningning Wang Lanxin Yue Pengfei Zhang Yongqiang Zhou Wei Zhou Yue Gao |
| author_facet | Gaofu Li Lei Zhou Huifang Deng Congshu Huang Ningning Wang Lanxin Yue Pengfei Zhang Yongqiang Zhou Wei Zhou Yue Gao |
| author_sort | Gaofu Li |
| collection | DOAJ |
| description | Celastrol, an active triterpenoid extracted from one of the most famous traditional Chinese medicines (TCMs), <i>Tripterygium wilfordii</i> 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. |
| first_indexed | 2024-03-09T11:28:07Z |
| format | Article |
| id | doaj.art-01c2fbe2b6ca40d19b3bc9e3da7edcb1 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T11:28:07Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-01c2fbe2b6ca40d19b3bc9e3da7edcb12023-11-30T23:56:56ZengMDPI AGPharmaceutics1999-49232022-12-011514810.3390/pharmaceutics15010048Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol’s Anti-Tumor Angiogenesis EffectGaofu Li0Lei Zhou1Huifang Deng2Congshu Huang3Ningning Wang4Lanxin Yue5Pengfei Zhang6Yongqiang Zhou7Wei Zhou8Yue Gao9Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaSchool of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, ChinaDepartment of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaSchool of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, ChinaDepartment of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaDepartment of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaDepartment of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaDepartment of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaDepartment of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaDepartment of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing 100850, ChinaCelastrol, an active triterpenoid extracted from one of the most famous traditional Chinese medicines (TCMs), <i>Tripterygium wilfordii</i> 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.https://www.mdpi.com/1999-4923/15/1/48celastroltumor angiogenesismitochondrion-targeted medicineOPA1 |
| spellingShingle | Gaofu Li Lei Zhou Huifang Deng Congshu Huang Ningning Wang Lanxin Yue Pengfei Zhang Yongqiang Zhou Wei Zhou Yue Gao Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol’s Anti-Tumor Angiogenesis Effect Pharmaceutics celastrol tumor angiogenesis mitochondrion-targeted medicine OPA1 |
| 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 | celastrol tumor angiogenesis mitochondrion-targeted medicine OPA1 |
| url | https://www.mdpi.com/1999-4923/15/1/48 |
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