Cryptotanshinone instigates ferroptosis to inhibit the development of tamoxifen-resistant breast cancer via the AMPK induced BECN1-SLC7A11 complex axis

Abstract

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.