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Ginsenoside-Rg2 exerts anti-cancer effects through ROS-mediated AMPK activation associated mitochondrial damage and oxidation in MCF-7 cells

Abstract

In this study, we investigated the anti-cancer effects of ginsenoside Rg2 (G-Rg2) and its underlying signaling pathways in breast cancer (BC) cells. G-Rg2 significantly induced cytotoxicity and reactive oxygen species (ROS) production in MCF-7 cells among various types of BC cells including HCC1428, T47D, and BT-549. G-Rg2 significantly inhibited protein and mRNA expression of cell cycle G1-S phase regulators, including p-Rb, cyclin D1, CDK4, and CDK6, whereas it enhanced the protein and mRNA expression of cell cycle arrest and apoptotic molecules including cleaved PARP, p21, p27, p53 and Bak through ROS production. These effects were abrogated by the antioxidant N-acetyl-I-cysteine, or NADPH oxidase inhibitors, such as diphenyleneiodonium chloride and apocynin. Interestingly, G-Rg2 induced mitochondrial damage by reducing the membrane potential. G-Rg2 further activated the ROS-sensor protein, AMPK and downstream targets of AMPK activation, including PGC-1α, FOXO1, and IDH2, and downregulated mTOR activation and antioxidant response element-driven luciferase activity. Together, our data demonstrate that G-Rg2 mediates anti-cancer effects by activating cell cycle arrest and signaling pathways related to mitochondrial damage-induced ROS production and apoptosis.

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Acknowledgements

This research was supported by National Research Foundation of Korea (KNRF-2019R1C1C100733112).

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Correspondence to Kyung-Sun Heo.

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Jeon, H., Jin, Y., Myung, CS. et al. Ginsenoside-Rg2 exerts anti-cancer effects through ROS-mediated AMPK activation associated mitochondrial damage and oxidation in MCF-7 cells. Arch. Pharm. Res. 44, 702–712 (2021). https://doi.org/10.1007/s12272-021-01345-3

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Keywords

  • AMPK
  • Breast cancer
  • Cell cycle
  • Ginsenoside-Rg2
  • Reactive oxygen species
  • Mitochondrial membrane potential