Alpha-fetoprotein inhibits autophagy to promote malignant behaviour in hepatocellular carcinoma cells by activating PI3K/AKT/mTOR signalling

Shanshan Wang,Dexi Chen,Yan Zhao,Qiaoyun Wang,Mingyue Zhu,Yuli Hou,Huiguo Ding,Junli Guo,Lei Li,Honglei Weng,Mengsen Li

doi:10.1038/s41419-018-1036-5

Abstract

Alpha-fetoprotein (AFP) has been recognized as a key regulator of cell proliferation in hepatocellular carcinoma (HCC). However, whether AFP functions in cancer cell autophagy remains unknown. This study investigated the effects of AFP on autophagy in HCC cells. The role of AFP was studied in two HCC cell lines, PLC/PRF/5 and HLE. Cell autophagy, apoptosis, proliferation, migration and invasion were analysed with Western blotting, co-immunoprecipitation (CoIP), immunofluorescence, animal models, MTT assays, flow cytometry (FCM), Cell Counting Kit (CCK)-8, and scratch and transwell assays. In PLC/PRF/5 cells, AFP interacted with PTEN and activated PI3K/Akt/mTOR signalling. In HLE cells, overexpressed AFP similarly interacted with PTEN, leading to PI3K/Akt/mTOR activation and reduced cell autophagy. When AFP was silenced in PLC/PRF/5 cells, cell proliferation, tumour growth, migration and invasion were inhibited, and the numbers of S-phase and apoptotic cells were increased. In contrast, AFP overexpression in HLE cells enhanced cell proliferation, migration and invasion and reduced apoptosis. AFP-dependent autophagy, proliferation, migration and apoptosis were inhibited by rapamycin. In summary, AFP plays critical roles in the inhibition of autophagy and apoptosis in HCC cells and promotes proliferation, migration and invasion. The role of AFP in autophagy inhibition in HCC cells may involve the activation of PI3K/Akt/mTOR signalling.

Highlights

Autophagy is an important lysosomal process, in which the degradation of cellular components serves to maintain cellular function and survival[1]
Laser scanning confocal microscopy demonstrated that AFP and PTEN colocalized in the cytoplasm of PLC/PRF/5 cells (Fig. 1b)
The data gathered in the present study suggest that AFP can regulate hepatocellular carcinoma cancer (HCC) cell autophagy by promoting PI3K/Akt/mTOR signalling by binding to PTEN

Summary

Introduction

Autophagy is an important lysosomal process, in which the degradation of cellular components serves to maintain cellular function and survival[1]. Autophagy may determine cell fate through complex signalling pathways and plays an important role in the pathophysiology of the liver. Liver function is highly dependent on autophagy[2]. Such dependence on autophagy is especially notable in several pathological liver diseases, such as hepatitis, alcohol/non-alcoholic fatty liver disease, drug-induced liver injury, and ischaemic injury[3,4]. Autophagy can regulate the proliferation and apoptosis of liver cells in different contexts, but its role in hepatocellular carcinoma cancer (HCC) is controversial[5]. Autophagy is a complex process that involves many signalling pathways. As is currently well known, the PI3K/Akt/mTOR pathway plays an important role in promoting cell autophagy[6]

Methods

Results

Conclusion