Mulberry Leaf Polyphenol Extract and Rutin Induces Autophagy Regulated by p53 in Human Hepatoma HepG2 Cells

Abstract

The edible leaves of the mulberry (Morus alba L.) plant are used worldwide. They contain abundant polyphenolic compounds with strong anticancer properties. We previously revealed that apoptosis was mediated in p53-negative Hep3B cells, and mulberry leaf polyphenol extract (MLPE) induced autophagy in p53-transfected Hep3B cells. However, how this autophagy is induced by p53 in human hepatoma HepG2 (p53 wild type) cells remains unclear. In the current study, MLPE induced autophagy, as demonstrated by enhanced acidic vesicular organelle staining, by upregulating beclin-1, increasing LC3-II conversion, and phosphorylating AMPK. In HepG2 cells, these processes were associated with p53. Western blot also revealed phosphatidylinositol-3 kinase (PI3K), p-AKT, and fatty acid synthase (FASN) suppression in MLPE-treated cells. Moreover, treatment with the p53 inhibitor pifithrin-α (PFT-α) inhibited autophagy and increased apoptotic response in MLPE-treated HepG2 cells. PFT-α treatment also reversed MLPE-induced PI3K, p-AKT, and FASN suppression. Thus, co-treatment with MLPE and PFT-α significantly increased caspase-3, caspase-8, and cytochrome c release, indicating that p53 deficiency caused the apoptosis. In addition, rutin, a bioactive polyphenol in MLPE, may affect autophagy in HepG2 cells. This study demonstrates that MLPE is a potential anticancer agent targeting autophagy and apoptosis in cells with p53 status. Moreover, this work provides insight into the mechanism of p53 action in MLPE-induced cytotoxicity in hepatocellular carcinoma.

The anti-obesity effect of mulberry leaf (Mori Folium) extracts was increased by bioconversion with Pectinex

“…These compounds were identified as neochlorogenic acid (#1, 5-CQA), chlorogenic acid (#2, 3-CQA) and cryptochlorogenic acid (#3, 4-CQA) from MS and UV spectra and the literature (Fig. 3 a) 49 – 51 . These compounds, as main compounds of MLE and BMLE, were quantified with calibration curves of each compound using HPLC analysis (Fig.…”

Mulberry leaf extract inhibits obesity and protects against diethylnitrosamine-induced hepatocellular carcinoma in rats

“…Our previous in vitro study clarified that mulberry leaf polyphenol extract activated the p53 pathway, which resulted in the downstream upregulation of phosphatidylinositol-3 kinase (PI3K), p -AKT, and fatty acid synthase in human hepatoma HepG2 cells. 60 Future in vivo studies should explore the signaling molecules involved in MLE’s anticancer effects.…”

Rutin Inhibits Hepatic and Pancreatic Cancer Cell Proliferation by Inhibiting CYP3A4 and GST

“…33 Furthermore, rutin has been shown to promote autophagy mediated by p53 in human hepatoma Hep-G2 cells, while others have shown that rutin inhibits Sorafenib-induced Chemoresistance and Autophagy in hepatocellular carcinoma through modulating the BANCR/ miRNA-590-5P/OLR1 axis in hepatocellular carcinoma. 25,38 In spite of great efforts done, the detailed pharmacological actions of rutin on tumor cells is still needs to be further clarified. Here, the inhibitory effect of rutin on five cell lines representing two different tumor types (hepatic, and pancreatic) were investigated in addition to normal pancreatic cell line.…”