1. Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signaling pathway in human breast cancer cells.
- Author
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Zhang HW, Hu JJ, Fu RQ, Liu X, Zhang YH, Li J, Liu L, Li YN, Deng Q, Luo QS, Ouyang Q, and Gao N
- Subjects
- Autophagy-Related Protein-1 Homolog metabolism, Cell Line, Tumor, Class Ib Phosphatidylinositol 3-Kinase, Down-Regulation, Humans, Intracellular Signaling Peptides and Proteins metabolism, Oncogene Protein v-akt metabolism, Ribosomal Protein S6 Kinases, 70-kDa metabolism, TOR Serine-Threonine Kinases metabolism, Antineoplastic Agents pharmacology, Apoptosis drug effects, Autophagy drug effects, Cell Proliferation drug effects, Flavonoids pharmacology, Phosphoinositide-3 Kinase Inhibitors, Signal Transduction drug effects
- Abstract
Anticancer activities of flavonoids derived from Tephroseris kirilowii (Turcz.) Holub. were evaluated in human cancer cells. We isolated and identified, for the first time, eight flavonoids from T. kirilowii and found that three of them (IH: isorhamnetin, GN: genkwanin, and Aca: acacetin) inhibited cell proliferation in a variety of human cancer cell lines. These active flavonoids caused cell cycle arrest at G2/M phase and induced apoptosis and autophagy in human breast cancer cells. Molecular docking revealed that these flavonoids dock in the ATP binding pocket of PI3Kγ. Importantly, treatment with these flavonoids decreased the levels of PI3Kγ-p110, phospho-PI3K, phospho-AKT, phospho-mTOR, phospho-p70S6K, and phospho-ULK. Pretreatment with PI3Kγ specific inhibitor AS605240 potentiated flavonoids-mediated inactivation of AKT, mTOR, p70S6K, ULK, and apoptosis. Taken together, these findings represent a novel mechanism by which downregulation of PI3Kγ-p110 and consequent interruption of PI3K/AKT/mTOR/p70S6K/ULK signaling pathway might play a critical functional role in these flavonoids-induced cell cycle arrest at G2/M phase, apoptosis, and autophagy. Our studies provide novel insights into the anticancer activities of selected flavonoids and their potential uses in anticancer therapy.
- Published
- 2018
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