Ginsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3/p53/NRF2 axis in colorectal cancer cells
Ginsenoside Rh3 (GRh3) is a seminatural product obtained by chemical processing after isolation from Chinese herbal medicine that has strong antitumor activity against human tumors. However, its antitumor role remains to be elucidated. The aim of this study is to explore the mechanisms underlying th...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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China Science Publishing & Media Ltd.
2023-04-01
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| Series: | Acta Biochimica et Biophysica Sinica |
| Subjects: | |
| Online Access: | https://www.sciengine.com/doi/10.3724/abbs.2023068 |
| _version_ | 1797635791365603328 |
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| author | Wu Yingchao Pi Dajin Zhou Shuyao Yi Zhongjia Dong Yangyang Wang Wuhong Ye Huan Chen Yiliu Zuo Qian Ouyang Mingzi |
| author_facet | Wu Yingchao Pi Dajin Zhou Shuyao Yi Zhongjia Dong Yangyang Wang Wuhong Ye Huan Chen Yiliu Zuo Qian Ouyang Mingzi |
| author_sort | Wu Yingchao |
| collection | DOAJ |
| description | Ginsenoside Rh3 (GRh3) is a seminatural product obtained by chemical processing after isolation from Chinese herbal medicine that has strong antitumor activity against human tumors. However, its antitumor role remains to be elucidated. The aim of this study is to explore the mechanisms underlying the tumor suppressive activity of GRh3 from the perspective of pyroptosis and ferroptosis. GRh3 eliminates colorectal cancer (CRC) cells by activating gasdermin D (GSDMD)-dependent pyroptosis and suppressing solute carrier family 7 member 11 (SLC7A11), resulting in ferroptosis activation through the Stat3/p53/NRF2 axis. GRh3 suppresses nuclear factor erythroid 2-related factor 2 (NRF2) entry into the nucleus, leading to the decrease of heme oxygenase 1 (HO-1) expression, which in turn promotes NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and caspase-1 expression. Finally, caspase-1 activates GSDMD-dependent pyroptosis. Furthermore, GRh3 prevents NRF2 from entering the nucleus, which suppresses SLC7A11, causing the depletion of glutathione (GSH) and accumulation of iron, lipid reactive oxygen species (ROS) and malondialdehyde (MDA), and eventually leading to ferroptosis in CRC cells. In addition, GRh3 effectively inhibits the proliferation of CRC cells in vitro and in nude mouse models. Collectively, GRh3 triggers pyroptotic cell death and ferroptotic cell death in CRC cells via the Stat3/p53/NRF2 axis with minimal harm to normal cells, showing great anticancer potential. |
| first_indexed | 2024-03-11T12:26:21Z |
| format | Article |
| id | doaj.art-13d4c90e45ad436794ec51eba7fa5878 |
| institution | Directory Open Access Journal |
| issn | 1672-9145 |
| language | English |
| last_indexed | 2024-03-11T12:26:21Z |
| publishDate | 2023-04-01 |
| publisher | China Science Publishing & Media Ltd. |
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| series | Acta Biochimica et Biophysica Sinica |
| spelling | doaj.art-13d4c90e45ad436794ec51eba7fa58782023-11-06T08:49:36ZengChina Science Publishing & Media Ltd.Acta Biochimica et Biophysica Sinica1672-91452023-04-015558760010.3724/abbs.202306820d259ccGinsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3/p53/NRF2 axis in colorectal cancer cellsWu Yingchao0Pi Dajin1Zhou Shuyao2Yi Zhongjia3Dong Yangyang4Wang Wuhong5Ye Huan6Chen Yiliu7Zuo Qian8Ouyang Mingzi9["School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"]["School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"]["College of Forestry and Landscape Architecture, South China Agricultural University, Guangzhou 510642, China"]["School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"]["Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"]["School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"]["School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"]["School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"]["MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China"]["School of Traditional Chinese Medicine, Jinan University, Guangzhou 510632, China"]Ginsenoside Rh3 (GRh3) is a seminatural product obtained by chemical processing after isolation from Chinese herbal medicine that has strong antitumor activity against human tumors. However, its antitumor role remains to be elucidated. The aim of this study is to explore the mechanisms underlying the tumor suppressive activity of GRh3 from the perspective of pyroptosis and ferroptosis. GRh3 eliminates colorectal cancer (CRC) cells by activating gasdermin D (GSDMD)-dependent pyroptosis and suppressing solute carrier family 7 member 11 (SLC7A11), resulting in ferroptosis activation through the Stat3/p53/NRF2 axis. GRh3 suppresses nuclear factor erythroid 2-related factor 2 (NRF2) entry into the nucleus, leading to the decrease of heme oxygenase 1 (HO-1) expression, which in turn promotes NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and caspase-1 expression. Finally, caspase-1 activates GSDMD-dependent pyroptosis. Furthermore, GRh3 prevents NRF2 from entering the nucleus, which suppresses SLC7A11, causing the depletion of glutathione (GSH) and accumulation of iron, lipid reactive oxygen species (ROS) and malondialdehyde (MDA), and eventually leading to ferroptosis in CRC cells. In addition, GRh3 effectively inhibits the proliferation of CRC cells in vitro and in nude mouse models. Collectively, GRh3 triggers pyroptotic cell death and ferroptotic cell death in CRC cells via the Stat3/p53/NRF2 axis with minimal harm to normal cells, showing great anticancer potential. https://www.sciengine.com/doi/10.3724/abbs.2023068pyroptosisferroptosisginsenoside Rh3Stat3/p53/NRF2 axiscolorectal cancer |
| spellingShingle | Wu Yingchao Pi Dajin Zhou Shuyao Yi Zhongjia Dong Yangyang Wang Wuhong Ye Huan Chen Yiliu Zuo Qian Ouyang Mingzi Ginsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3/p53/NRF2 axis in colorectal cancer cells Acta Biochimica et Biophysica Sinica pyroptosis ferroptosis ginsenoside Rh3 Stat3/p53/NRF2 axis colorectal cancer |
| title | Ginsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3/p53/NRF2 axis in colorectal cancer cells |
| title_full | Ginsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3/p53/NRF2 axis in colorectal cancer cells |
| title_fullStr | Ginsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3/p53/NRF2 axis in colorectal cancer cells |
| title_full_unstemmed | Ginsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3/p53/NRF2 axis in colorectal cancer cells |
| title_short | Ginsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3/p53/NRF2 axis in colorectal cancer cells |
| title_sort | ginsenoside rh3 induces pyroptosis and ferroptosis through the stat3 p53 nrf2 axis in colorectal cancer cells |
| topic | pyroptosis ferroptosis ginsenoside Rh3 Stat3/p53/NRF2 axis colorectal cancer |
| url | https://www.sciengine.com/doi/10.3724/abbs.2023068 |
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