Mengning Zhang , Hang Chen , Lujia Zhang , Aini Yuan , Jing Liu , Qi Wang , Tiantian Lei , Hong Zhao
{"title":"隐丹参酮诱导铁下垂通过AMPK诱导BECN1-SLC7A11复合体轴抑制他莫昔芬耐药乳腺癌的发展","authors":"Mengning Zhang , Hang Chen , Lujia Zhang , Aini Yuan , Jing Liu , Qi Wang , Tiantian Lei , Hong Zhao","doi":"10.1016/j.yexcr.2025.114726","DOIUrl":null,"url":null,"abstract":"<div><div>The resistance of oestrogen receptor-positive (ER+) breast cancer to tamoxifen (TAM) therapy represents a significant challenge in the clinical management of ER + breast cancer. It has been demonstrated that tamoxifen-resistant breast cancer is sensitive to ferroptosis. Consequently, the targeted intervention of Solute Carrier Family 7 Member 11 (SLC7A11) to promote ferroptosis represents a promising means of treating this form of cancer. Cryptotanshinone (CTS), a fat-soluble diterpene derivative extracted from Salvia miltiorrhiza, has been demonstrated to possess favorable anti-breast cancer activity. However, it remains unclear whether CTS is effective against tamoxifen-resistant breast cancer. The objective of this study was to ascertain whether CTS-induced ferroptosis could be employed to inhibit tamoxifen-resistant breast cancer, and to elucidate the potential mechanism of action. CTS was observed to inhibit the proliferation of TAM-resistant MCF-7 cells, and this effect could be synergistically amplified by co-treatment with TAM. Furthermore, CTS was also demonstrated to increase the sensitivity of TAM-resistant MCF-7 cells to TAM. Additionally, CTS has been observed to promote ferroptosis in TAM-resistant MCF-7 cells, resulting in elevated levels of the associated indices 4 Hydroxynonenal (4HNE), Lipid Reactive oxygen species (ROS), ROS and Fe<sup>2+</sup>, while concurrently reducing the levels of SLC7A11 and Glutathione peroxidase 4 (GPX4). Further studies demonstrated that CTS promoted TAM-resistant MCF-7 cell ferroptosis based on the formation of the BECN1-SLC7A11 complex, which resulted in a decrease in SLC7A11. Validation experiments demonstrated that CTS-induced BECN1-SLC7A11 complex formation is dependent on AMPK activation. Xenotumour transplantation experiments revealed that CTS combined with TAM inhibits TAM-resistant breast cancer and promotes ferroptosis through the AMPK/BECN1/SLC7A11 axis. In conclusion, CTS retarded the growth of TAM-resistant breast cancer tumours by activating AMPK to promote the formation of the BECN1-SLC7A11 complex and inhibiting the expression of SLC7A11, thereby inducing ferroptosis.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"451 2","pages":"Article 114726"},"PeriodicalIF":3.5000,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cryptotanshinone instigates ferroptosis to inhibit the development of tamoxifen-resistant breast cancer via the AMPK induced BECN1-SLC7A11 complex axis\",\"authors\":\"Mengning Zhang , Hang Chen , Lujia Zhang , Aini Yuan , Jing Liu , Qi Wang , Tiantian Lei , Hong Zhao\",\"doi\":\"10.1016/j.yexcr.2025.114726\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The resistance of oestrogen receptor-positive (ER+) breast cancer to tamoxifen (TAM) therapy represents a significant challenge in the clinical management of ER + breast cancer. It has been demonstrated that tamoxifen-resistant breast cancer is sensitive to ferroptosis. Consequently, the targeted intervention of Solute Carrier Family 7 Member 11 (SLC7A11) to promote ferroptosis represents a promising means of treating this form of cancer. Cryptotanshinone (CTS), a fat-soluble diterpene derivative extracted from Salvia miltiorrhiza, has been demonstrated to possess favorable anti-breast cancer activity. However, it remains unclear whether CTS is effective against tamoxifen-resistant breast cancer. The objective of this study was to ascertain whether CTS-induced ferroptosis could be employed to inhibit tamoxifen-resistant breast cancer, and to elucidate the potential mechanism of action. CTS was observed to inhibit the proliferation of TAM-resistant MCF-7 cells, and this effect could be synergistically amplified by co-treatment with TAM. Furthermore, CTS was also demonstrated to increase the sensitivity of TAM-resistant MCF-7 cells to TAM. Additionally, CTS has been observed to promote ferroptosis in TAM-resistant MCF-7 cells, resulting in elevated levels of the associated indices 4 Hydroxynonenal (4HNE), Lipid Reactive oxygen species (ROS), ROS and Fe<sup>2+</sup>, while concurrently reducing the levels of SLC7A11 and Glutathione peroxidase 4 (GPX4). Further studies demonstrated that CTS promoted TAM-resistant MCF-7 cell ferroptosis based on the formation of the BECN1-SLC7A11 complex, which resulted in a decrease in SLC7A11. Validation experiments demonstrated that CTS-induced BECN1-SLC7A11 complex formation is dependent on AMPK activation. Xenotumour transplantation experiments revealed that CTS combined with TAM inhibits TAM-resistant breast cancer and promotes ferroptosis through the AMPK/BECN1/SLC7A11 axis. In conclusion, CTS retarded the growth of TAM-resistant breast cancer tumours by activating AMPK to promote the formation of the BECN1-SLC7A11 complex and inhibiting the expression of SLC7A11, thereby inducing ferroptosis.</div></div>\",\"PeriodicalId\":12227,\"journal\":{\"name\":\"Experimental cell research\",\"volume\":\"451 2\",\"pages\":\"Article 114726\"},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2025-08-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental cell research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S001448272500326X\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental cell research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S001448272500326X","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Cryptotanshinone instigates ferroptosis to inhibit the development of tamoxifen-resistant breast cancer via the AMPK induced BECN1-SLC7A11 complex axis
The resistance of oestrogen receptor-positive (ER+) breast cancer to tamoxifen (TAM) therapy represents a significant challenge in the clinical management of ER + breast cancer. It has been demonstrated that tamoxifen-resistant breast cancer is sensitive to ferroptosis. Consequently, the targeted intervention of Solute Carrier Family 7 Member 11 (SLC7A11) to promote ferroptosis represents a promising means of treating this form of cancer. Cryptotanshinone (CTS), a fat-soluble diterpene derivative extracted from Salvia miltiorrhiza, has been demonstrated to possess favorable anti-breast cancer activity. However, it remains unclear whether CTS is effective against tamoxifen-resistant breast cancer. The objective of this study was to ascertain whether CTS-induced ferroptosis could be employed to inhibit tamoxifen-resistant breast cancer, and to elucidate the potential mechanism of action. CTS was observed to inhibit the proliferation of TAM-resistant MCF-7 cells, and this effect could be synergistically amplified by co-treatment with TAM. Furthermore, CTS was also demonstrated to increase the sensitivity of TAM-resistant MCF-7 cells to TAM. Additionally, CTS has been observed to promote ferroptosis in TAM-resistant MCF-7 cells, resulting in elevated levels of the associated indices 4 Hydroxynonenal (4HNE), Lipid Reactive oxygen species (ROS), ROS and Fe2+, while concurrently reducing the levels of SLC7A11 and Glutathione peroxidase 4 (GPX4). Further studies demonstrated that CTS promoted TAM-resistant MCF-7 cell ferroptosis based on the formation of the BECN1-SLC7A11 complex, which resulted in a decrease in SLC7A11. Validation experiments demonstrated that CTS-induced BECN1-SLC7A11 complex formation is dependent on AMPK activation. Xenotumour transplantation experiments revealed that CTS combined with TAM inhibits TAM-resistant breast cancer and promotes ferroptosis through the AMPK/BECN1/SLC7A11 axis. In conclusion, CTS retarded the growth of TAM-resistant breast cancer tumours by activating AMPK to promote the formation of the BECN1-SLC7A11 complex and inhibiting the expression of SLC7A11, thereby inducing ferroptosis.
期刊介绍:
Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.