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
Scientific RepoRts |
through downregulation of PI3K? mediated PI3K/AKT/mTOR/p70S6K/
Hong-Wei Zhang
Jin-Jiao Hu
Ruo-Qiu Fu
Xin Liu
Yan-Hao Zhang
Jing Li
Lei Liu
Yu-Nong Li
Qin Deng
Qing-Song Luo
Qin Ouyang
Ning Gao
OPEN 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 PI3K?. Importantly, treatment with these flavonoids decreased the levels of PI3K?-p110, phospho-PI3K, phospho-AKT, phospho-mTOR, phospho-p70S6K, and phospho-ULK. Pretreatment with PI3K? 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 PI3K?-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.
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Traditional Chinese medicines have been recently recognized as a new source of anticancer drugs and
neoadjuvant chemotherapy to enhance the efficacy of chemotherapy and to alleviate the side effects of cancer
chemotherapy1,2. However, the mechanisms of actions are still largely unknown. Flavonoids are a group of more than
4000 polyphenolic compounds that occur naturally in a variety of plant origin3. A growing number of studies
indicate that flavonoids or flavonoid derivatives play critical roles in cancer chemoprevention and chemotherapy.
A number of epidemiological studies indicate that high flavonoid intake may be correlated with a decreased risk
of cancer, and provide evidence for the protective roles of flavonoids against cancer4,5. In vitro studies indicate that
anticancer activities of flavonoids may be related to inhibiting cell proliferation, adhesion, and invasion, inducing
cell differentiation, cell cycle arrest, and apoptosis, etc.6,7. In vivo studies demonstrate that flavonoids could inhibit
carcinogenesis by affecting the molecular events in the initiation, promotion, and progression stages8. The clinical
trials of flavonoids in human have been exploited to achieve cancer preventive or therapeutic effects9. Based on
these results, flavonoids could be developed as promising agents for cancer chemoprevention and chemotherapy.
Tephroseris kirilowii Turcz. Holub (Compositae) is a perennial herb widely distributed in China10. The whole
plant of T. kirilowii exhibit a wide range of biological activities against many types of diseases such as urethral
infection, oedema, eczema, scabies, vaginal trichomoniasis, and leukaemia in Chinese-folk medicine11?13. The
main constituents of T. kirilowii are alkaloids and flavonoids. Recently, natural compounds from flavonoids
have been found to exhibit anti-cancer effects through multiple molecular mechanisms that involve the
modulation of apoptosis, cell cycle arrest and autophagy14?16. However, the types of flavonoids in T. kirilowii have
not been characterized, nor have the mechanisms of flavonoids-mediated anticancer activities been elucidated
in depth. The purpose of the present study is to isolate and characterize the structures of flavonoids from T.
kirilowii, to evaluate the effects of flavonoids on anticancer activities, and to elucidate the molecular
mechanisms of flavonoids-mediated anticancer activities. In this study, we isolated and identified, for the first time,
eight flavonoids from T. kirilowii: isorhamnetin, isorhamnetin-3- glucoside, kaempferol, apigenin, acacetin,
chrysin, 7,8-dihydroxyflavanone, and genkwanin. Using bioactivity-guided screening of selected flavonoid
compounds isolated from T. kirilowii, we found that three compounds among these flavonoids exhibited
anticancer activities. We provide the evidence that isorhamnetin, genkwanin, and acacetin inhibited cell proliferation
in human cancer cells through cell cycle arrest at G2/M phase and induction of apoptotic and autophagic cell
death. Molecular docking revealed that these flavonoids dock in the ATP binding pocket of PI3K?. Mechanistic
studies revealed that interruption of the PI3K/Akt/mTOR/ULK signaling pathway plays a critical role in
these flavonoids-mediated cell cycle arrest and induction of apoptotic and autophagic cell death via reducing
PI3K?-p110 expression. Our studies provide novel insights into the anticancer activities of selected flavonoids
and their potential use (...truncated)