Sotetsuflavone Induces Autophagy in Non-Small Cell Lung Cancer Through Blocking PI3K/Akt/mTOR Signaling Pathway in Vivo and in Vitro

Abstract

Non-small cell lung cancer (NSCLC) is a globally scaled disease with a high incidence and high associated mortality rate. Autophagy is one of the important physiological activities that helps to control cell survival, influences the dynamics of cell death, and which plays a crucial role in the pathophysiology of NSCLC. Sotetsuflavone is a naturally derived and occurring flavonoid, and previous studies have demonstrated that sotetsuflavone possesses potential anti-cancer activities. However, whether or not sotetsuflavone induces autophagy, as well as has effects and influences cell death in NSCLC cells remains unclear. Thus, in our study, we examined and elucidated the roles and underlying mechanisms of sotetsuflavone upon the dynamics of autophagy in NSCLC in vivo and in vitro. The results indicated that sotetsuflavone was able to inhibit proliferation, migration, and invasion of NSCLC cells. Mechanistically, sotetsuflavone was able to induce apoptosis by increasing the levels of expression of cytochrome C, cleaved-caspase 3, cleaved-caspase 9, and Bax, and contrastingly decreased levels of expression of Bcl-2. In addition, we also found that decreased levels of expression of cyclin D1 and CDK4 caused arrest of the G0/G1 phases of the cell cycle. Furthermore, we also found that sotetsuflavone could induce autophagy which in turn can play a cytoprotective effect on apoptosis in NSCLC. Sotetsuflavone-induced autophagy appeared related to the blocking of the PI3K/Akt/ mTOR pathway. Our in vivo study demonstrated that sotetsuflavone significantly inhibited the growth of xenograft model inoculated A549 tumor with high a degree of safety. Taken together, these findings suggest that sotetsuflavone induces autophagy in NSCLC cells through its effects upon blocking of the PI3K/Akt/mTOR signaling pathways. Our study may provide a theoretical basis for future clinical applications of sotetsuflavone and its use as a chemotherapeutic agent for treatment of NSCLC.

Fisetin inhibits inflammation and induces autophagy by mediating PI3K/AKT/mTOR signaling in LPS-induced RAW264.7 cells

“…Numerous natural products have been proved to suppress cancer cells by targeting the PI3K/AKT/mTOR-mediated autophagy ( 53 ). Wang et al found a natural source of flavonoid, sotetsuflavone, which could induce autophagy by blocking PI3K/AKT/mTOR pathways in NSCLC cells ( 54 ). Besides, the PI3K/AmKT/mTOR signaling pathway is involved in the regulation of inflammation, which is usually related to the activation of TLRs/NF-κB, cytokine receptor and tyrosine kinase receptor signals ( 55 ).…”

The Local Anesthetic Bupivacaine Inhibits the Progression of Non-Small Cell Lung Cancer by Inducing Autophagy Through Akt/mTOR Signaling

“…Ganoderic acid DM provokes autophagic apoptosis by repressing the PI3K/Akt/mTOR signaling in NSCLC cells ( 29 ). Sotetsuflavone promotes autophagy in NSCLC cells by inhibiting PI3K/Akt/mTOR axis in vitro and in vivo ( 30 ). An active drug sensitizing agent improves gefitinib therapy by up-regulating autophagy and down-regulating PI3K/Akt/mTOR signaling in NSCLC ( 31 ).…”

A Network Pharmacology Approach to Investigate the Anticancer Mechanism and Potential Active Ingredients of Rheum palmatum L. Against Lung Cancer via Induction of Apoptosis

“…Therefore, inhibiting the proliferation and inducing apoptosis of lung cancer has become a feasible strategy for the treatment of lung cancer. A large number of studies have also found that mechanisms of many natural anticancer drugs against lung cancer are related to the regulation of different signaling pathways to inhibit the proliferation of lung cancer cells and induce the apoptosis of lung cancer cells ( Wang S. et al., 2019 ; Han et al., 2020 ; Hu et al., 2020 ). Therefore, we subsequently designed corresponding in vitro experiments in order to prove the prediction results of network pharmacology.…”