Mulberry fruits extracts induce apoptosis and autophagy of liver cancer cell and prevent hepatocarcinogenesis in vivo

Kwok-Chui Cheng ^a,1, Chau-Jong Wang ^b,c,j,1, Yun-Ching Chang ^b,c,j,Tung-Wei Hung ^c,d, Chun-Jung Lai ^b, Chi-Wen Kuo ^e,f,g,h,

Hui-Pei Huang ^b,c,i,*

a Department of Colorectal Surgery, Dali Jen-Ai Hospital, Taichung, Taiwan

b Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan

c Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan

d Department of Nephrology, Chung Shan Medical University Hospital, Taichung, Taiwan

e Department of Pharmacy, Dali Jen-Ai Hospital, Taichung, Taiwan

f School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan

g Basic Medical Education Center, Central Taiwan University of Science and Technology, Taichung, Taiwan

h Department of Health Policy and Management, Chung Shan Medical University, Taichung, Taiwan

i Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan

j Department of Health Diet and Industry Management, Health Care and Management College, Chung Shan Medical University, Taiwan

Hepatocellular carcinoma (HCC) is one of the most common malignancies in Taiwan. Many risks factors induce liver chronic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Mulberry fruits containing polyphenols to remove free radicals and mitigate inflammation has been reported to not only against gastric cancer, melanoma and leukemia but also prevent liver injury induced by alcohol or CCl4 in previous researches. The aim of this study is to examine whether Mulberry could inhibit hepatocarcinogenesis. In animal experiment, diethylnitrosamine (DEN) was used to induce hepatic tumorgenesis. After injecting DEN, the rats treated with mulberry water extracts (MWE) had less and smaller tumor than others without MWE. Moreover, MWE reduced the serum ALT and AST, HCC marker, cleavage caspases, Ser-15-p53 and Ser46-p53 induced by DEN. Further, we observed that mulberry polyphenol extracts (MPE) inhibited the cell growth of HepG2 cell and Hep3B cell. By using flow cytometry and western blotting methods, MPE induced HepG2 cell apoptosis by increase subG1 cells and the elevated expression of caspase-3/8/9. Instead of apoptosis, MPE caused Hep3B cells autophagy by inhibiting Akt and mTOR phosphorylation. Comprehensively, mulberry extracts has a potential to be a health supplement to prevent hepatocarcinogenesis in the future.

Keywords: Apoptosis; Autophagy; Hepatocellular carcinoma; Mulberry water extracts; Polyphenol

https://doi.org/10.1016/j.jfda.2019.06.002.

(http://www.sciencedirect.com/science/article/pii/S1021949819300523)