Amyloid precursor protein regulates 5-fluorouracil resistance in human hepatocellular carcinoma cells by inhibiting the mitochondrial apoptotic pathway

• Published in: Journal of Zhejiang University. B. Science Vol. 21; no. 3; pp. 234 - 245
• Main Authors: Wu, Xiao-long, Chen, Ying, Kong, Wen-cui, Zhao, Zhong-quan
• Format: Journal Article
• Language: English
• Published: Hangzhou Zhejiang University Press 01.03.2020; Springer Nature B.V
• Subjects: 5-Fluorouracil; Alzheimer's disease; Amyloid beta-Protein Precursor - physiology; Amyloid precursor protein; Apoptosis; Apoptosis - drug effects; Bcl-2 protein; Bcl-x protein; bcl-X Protein - genetics; Biomedical and Life Sciences; Biomedicine; Biotechnology; Carcinoma, Hepatocellular - drug therapy; Cell cycle; Cell Line, Tumor; Cell membranes; Drug resistance; Drug Resistance, Neoplasm; Fluorouracil - pharmacology; Gene expression; Hepatocellular carcinoma; Hepatocytes; Humans; Liver; Liver cancer; Liver Neoplasms - drug therapy; Lymphocytes B; Lymphoma; Membrane proteins; Metastases; Mitochondria; Mitochondria - physiology; Morbidity; Neurodegenerative diseases; Pathogenesis; Polymerase chain reaction; Precursors; Proteins; Proto-Oncogene Proteins c-bcl-2 - genetics; Reverse transcription; Tumors; Western blotting; 5-Fluorouracil resistance; 线粒体凋亡通路; 淀粉样前体蛋白; 肝细胞癌; 5-氟尿嘧啶抗性; Hepatocellular carcinoma; R735.7; Mitochondrial apoptotic pathway; Amyloid precursor protein; Amyloid precursor protein; 5-Fluorouracil resistance; Mitochondrial apoptotic pathway; Hepatocellular carcinoma
• ISSN: 1673-1581; 1862-1783
• DOI: 10.1631/jzus.B1900413

Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality globally. It accounts for the majority of primary liver cancer cases. Amyloid precursor protein (APP), a cell membrane protein, plays a vital role in the pathogenesis of Alzheimer’s disease, and has been found to be implicated in tumor growth and metastasis. Therefore, to understand the relationship between APP and 5-fluorouracil (5-FU) resistance in liver cancer, Cell Counting Kit-8, apoptosis and cell cycle assays, western blotting, and reverse transcription-quantitative polymerase chain reaction (qPCR) analysis were performed. The results demonstrated that APP expression in Bel7402-5-FU cells was significantly up-regulated, as compared with that in Bel7402 cells. Through successful construction of APP-silenced (siAPP) and overexpressed (OE) Bel7402 cell lines, data revealed that the Bel7402-APP 751-OE cell line was insensitive, while the Bel7402-siAPP cell line was sensitive to 5-FU in comparison to the matched control group. Furthermore, APP overexpression decreased, while APP silencing increased 5-FU-induced apoptosis in Bel7402 cells. Mechanistically, APP overexpression and silencing can regulate the mitochondrial apoptotic pathway and the expression of apoptotic suppressor genes (B-cell lymphoma-2 ( Bcl-2 ) and B-cell lymphoma-extra large ( Bcl-xl )). Taken together, these results preliminarily revealed that APP overexpression contributes to the resistance of liver cancer cells to 5-FU, providing a new perspective for drug resistance.