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

Exp Cell Res. 2025 Aug 15;451(2):114726. doi: 10.1016/j.yexcr.2025.114726. Epub 2025 Aug 26.

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.

Keywords: AMPK; BECN1; Cryptotanshinone; Ferroptosis; Tamoxifen-resistant breast cancer.

MeSH terms

  • AMP-Activated Protein Kinases* / metabolism
  • Amino Acid Transport System y+* / genetics
  • Amino Acid Transport System y+* / metabolism
  • Animals
  • Beclin-1* / genetics
  • Beclin-1* / metabolism
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / metabolism
  • Breast Neoplasms* / pathology
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Female
  • Ferroptosis* / drug effects
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Phenanthrenes* / pharmacology
  • Reactive Oxygen Species / metabolism
  • Tamoxifen* / pharmacology

Substances

  • Beclin-1
  • Tamoxifen
  • Phenanthrenes
  • cryptotanshinone
  • Amino Acid Transport System y+
  • SLC7A11 protein, human
  • BECN1 protein, human
  • AMP-Activated Protein Kinases
  • Reactive Oxygen Species