Study on the Antitumor Mechanism of Tanshinone IIA In Vivo and In Vitro through the Regulation of PERK-ATF4-HSPA5 Pathway-Mediated Ferroptosis
As a traditional Chinese medicine, <i>Salvia miltiorrhiza Bunge</i> was first recorded in the Shennong Materia Medica Classic and is widely used to treat “the accumulation of symptoms and masses”. The main active ingredient of <i>Salvia miltiorrhiza Bunge</i>, Tanshinone IIA...
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MDPI AG
2024-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/29/7/1557 |
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| author | Chunxiang Guo Wei Zhao Wei Wang Zheng Yao Wenhui Chen Xiaoyi Feng |
| author_facet | Chunxiang Guo Wei Zhao Wei Wang Zheng Yao Wenhui Chen Xiaoyi Feng |
| author_sort | Chunxiang Guo |
| collection | DOAJ |
| description | As a traditional Chinese medicine, <i>Salvia miltiorrhiza Bunge</i> was first recorded in the Shennong Materia Medica Classic and is widely used to treat “the accumulation of symptoms and masses”. The main active ingredient of <i>Salvia miltiorrhiza Bunge</i>, Tanshinone IIA (TIIA), has shown anti-inflammatory, antitumor, antifibrosis, antibacterial, and antioxidative activities, etc. In this study, the results showed that TIIA could inhibit the proliferation and migration of HepG2 cells and downregulate glutathione (GSH) and Glutathione Peroxidase 4 (GPX4) levels; besides, TIIA induced the production of Reactive Oxygen Species (ROS), and upregulated the total iron content. Based on network pharmacology analysis, the antitumor effect of TIIA was found to be focused on the endoplasmic reticulum (ER)-mediated ferroptosis signaling pathway, with protein kinase R (PKR)-like ER kinase (PERK)-activating transcription factor 4 (ATF4)-heat shock 70 kDa protein 5 (HSPA5) as the main pathway. Herein, TIIA showed typical ferroptosis characteristics, and a ferroptosis inhibitor (ferrostatin-1) was used to verify the effect. The antitumor effects of TIIA, occurring through the inhibition of the PERK-ATF4-HSPA5 pathway, were further observed in vivo as significantly inhibited tumor growth and the improved pathological morphology of tumor tissue in H22-bearing mice. In summary, the antitumor mechanism of TIIA might be related to the downregulation of the activation of PERK-ATF4-HSPA5 pathway-mediated ferroptosis. |
| first_indexed | 2024-04-24T10:38:43Z |
| format | Article |
| id | doaj.art-12ead4ab73304670b04462784f40d2d2 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-24T10:38:43Z |
| publishDate | 2024-03-01 |
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| record_format | Article |
| series | Molecules |
| spelling | doaj.art-12ead4ab73304670b04462784f40d2d22024-04-12T13:23:23ZengMDPI AGMolecules1420-30492024-03-01297155710.3390/molecules29071557Study on the Antitumor Mechanism of Tanshinone IIA In Vivo and In Vitro through the Regulation of PERK-ATF4-HSPA5 Pathway-Mediated FerroptosisChunxiang Guo0Wei Zhao1Wei Wang2Zheng Yao3Wenhui Chen4Xiaoyi Feng5School of Basic Medicine, Yunnan University of Chinese Medicine, Kunming 650500, ChinaSchool of Basic Medicine, Yunnan University of Chinese Medicine, Kunming 650500, ChinaSchool of Basic Medicine, Yunnan University of Chinese Medicine, Kunming 650500, ChinaSchool of Basic Medicine, Yunnan University of Chinese Medicine, Kunming 650500, ChinaSchool of Basic Medicine, Yunnan University of Chinese Medicine, Kunming 650500, ChinaSchool of Basic Medicine, Yunnan University of Chinese Medicine, Kunming 650500, ChinaAs a traditional Chinese medicine, <i>Salvia miltiorrhiza Bunge</i> was first recorded in the Shennong Materia Medica Classic and is widely used to treat “the accumulation of symptoms and masses”. The main active ingredient of <i>Salvia miltiorrhiza Bunge</i>, Tanshinone IIA (TIIA), has shown anti-inflammatory, antitumor, antifibrosis, antibacterial, and antioxidative activities, etc. In this study, the results showed that TIIA could inhibit the proliferation and migration of HepG2 cells and downregulate glutathione (GSH) and Glutathione Peroxidase 4 (GPX4) levels; besides, TIIA induced the production of Reactive Oxygen Species (ROS), and upregulated the total iron content. Based on network pharmacology analysis, the antitumor effect of TIIA was found to be focused on the endoplasmic reticulum (ER)-mediated ferroptosis signaling pathway, with protein kinase R (PKR)-like ER kinase (PERK)-activating transcription factor 4 (ATF4)-heat shock 70 kDa protein 5 (HSPA5) as the main pathway. Herein, TIIA showed typical ferroptosis characteristics, and a ferroptosis inhibitor (ferrostatin-1) was used to verify the effect. The antitumor effects of TIIA, occurring through the inhibition of the PERK-ATF4-HSPA5 pathway, were further observed in vivo as significantly inhibited tumor growth and the improved pathological morphology of tumor tissue in H22-bearing mice. In summary, the antitumor mechanism of TIIA might be related to the downregulation of the activation of PERK-ATF4-HSPA5 pathway-mediated ferroptosis.https://www.mdpi.com/1420-3049/29/7/1557Tanshinone IIAendoplasmic reticulum stressPERK-ATF4-HSPA5 pathwayferroptosisanti-hepatoma |
| spellingShingle | Chunxiang Guo Wei Zhao Wei Wang Zheng Yao Wenhui Chen Xiaoyi Feng Study on the Antitumor Mechanism of Tanshinone IIA In Vivo and In Vitro through the Regulation of PERK-ATF4-HSPA5 Pathway-Mediated Ferroptosis Molecules Tanshinone IIA endoplasmic reticulum stress PERK-ATF4-HSPA5 pathway ferroptosis anti-hepatoma |
| title | Study on the Antitumor Mechanism of Tanshinone IIA In Vivo and In Vitro through the Regulation of PERK-ATF4-HSPA5 Pathway-Mediated Ferroptosis |
| title_full | Study on the Antitumor Mechanism of Tanshinone IIA In Vivo and In Vitro through the Regulation of PERK-ATF4-HSPA5 Pathway-Mediated Ferroptosis |
| title_fullStr | Study on the Antitumor Mechanism of Tanshinone IIA In Vivo and In Vitro through the Regulation of PERK-ATF4-HSPA5 Pathway-Mediated Ferroptosis |
| title_full_unstemmed | Study on the Antitumor Mechanism of Tanshinone IIA In Vivo and In Vitro through the Regulation of PERK-ATF4-HSPA5 Pathway-Mediated Ferroptosis |
| title_short | Study on the Antitumor Mechanism of Tanshinone IIA In Vivo and In Vitro through the Regulation of PERK-ATF4-HSPA5 Pathway-Mediated Ferroptosis |
| title_sort | study on the antitumor mechanism of tanshinone iia in vivo and in vitro through the regulation of perk atf4 hspa5 pathway mediated ferroptosis |
| topic | Tanshinone IIA endoplasmic reticulum stress PERK-ATF4-HSPA5 pathway ferroptosis anti-hepatoma |
| url | https://www.mdpi.com/1420-3049/29/7/1557 |
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