Preliminary Study On The Molecular Mechanism Of Autophagy Induced By AKR1B10-mediated Endoplasmic Reticulum Stress In Human Colon Cancer Cells

Colorectal cancer is one of the most common malignant tumors of the digestive tract,with extremely high morbidity and mortality.In the process of colorectal cancer,the proliferation of cancer cells increases and the surrounding incomplete angiogenesis can trigger endoplasmic reticulum stress and cause autophagy.Endoplasmic reticulum stress and autophagy are both key processes to maintain the homeostasis of tumor cells,as well as important responses to external pressure stimuli.AKR1B10(Aldo-keto reductase family 1 member B10)is involved in the occurrence and development of colorectal cancer and the formation of chemotherapeutic drug resistance.It is a potential new target for the diagnosis and treatment of colorectal cancer.This project focuses on the AKR1B10 gene and endoplasmic reticulum stress-induced autophagy in colon cancer,and explores its molecular mechanism and possible signal pathways,providing new information for the diagnosis and treatment of colorectal cancer based on AKR1B10.The previous research found that AKR1B10 in human colon cancer cell HT29 can inhibit autophagy caused by glucose starvation.In this study,BIP interacts with AKR1B10 was detected by proteomics sequencing.Then three human colon cancer cell lines,HT29,HCT116 and HCT8 were selected as models,and cell models of knockdown,rescue and overexpressing AKR1B10 were constructed in the three cell lines by molecular cloning technology.The tunicamycin was used to stimulate the endoplasmic reticulum stress,and the autophagy caused by the endoplasmic reticulum stress caused by AKR1B10 in three human colon cancer cells was observed by qRT-PCR,western blotting,transmission electron microscopy,and confocal microscopy.The possible molecular mechanism of AKR1B10 in inhibiting autophagy caused by endoplasmic reticulum stress was discussed.The experimental results show that AKR1B10 interacts with BIP,and AKR1B10 can inhibit autophagy induced by endoplasmic reticulum stress in three colon cancer cells.The phosphorylation of PERK is enhanced after AKR1B10 is knocked down in the cells,and the phosphorylation of PERK is weakened after rescue of AKR1B10.The use of PERK phosphorylation inhibitors can reverse the enhanced autophagy after knocking down AKR1B10.At the same time,ARK1B10 inhibited the expression of ATF4 and CHOP downstream of the PERK pathway at the mRNA and protein levels.From this,it can be concluded that:1.AKR1B10 interacts with BIP.2.AKR1B10 inhibited autophagy induced by endoplasmic reticulum stress in HT29,HCT116 and HCT8 cells.3.AKR1B10 affected autophagy induced by endoplasmic reticulum stress through inhibition of PERK phosphorylation.4.AKR1B10 inhibited ATF4 and CHOP downstream of PERK.The present study is centered on AKR1B10 and endoplasmic reticulum stress-induced autophagy,and provides a preliminary investigation of the molecular mechanism of its possible effects,which provides a theoretical basis for AKR1B10-based colorectal cancer therapy.