AKR1B10 Inhibitor Epalrestat Facilitates Sorafenib-Induced Apoptosis and Autophagy Via Targeting the mTOR Pathway in Hepatocellular Carcinoma

Abstract

Sorafenib is the standard systemic treatment for advanced hepatocellular carcinoma (HCC), and improving its therapeutic effects is crucial for addressing cancer aggression. We previously reported that epalrestat, an aldo-keto reductase 1B10 inhibitor, enhanced sorafenib's inhibitory effects on HCC xenograft in nude mice. This study aimed to elucidate the mechanism of epalrestat's anti-tumour enhancing effects on sorafenib. HepG2 cells were treated with sorafenib, epalrestat, and their combination. Cell proliferation was assessed with Cell Counting Kit-8 and colony formation assays. AKR1B10 supernate concentration and enzyme activity were detected by ELISA assay and the decrease of optical density of NADPH at 340 nm. Cell cycle and apoptosis analyses were performed with flow cytometry. Western blots clarified the molecular mechanism underlying effects on cell cycle, apoptosis, and autophagy. The anti-tumour mechanism was then validated in vivo through TUNEL and immunohistochemistry staining of HCC xenograft sections. Epalrestat combined with sorafenib inhibited HepG2 cellular proliferation in vitro, arrested the cell cycle at G0/G1, and promoted apoptosis and autophagy. Treatment with a specific mTOR activator MHY-1485 increased mTOR phosphorylation, while suppressing apoptosis and autophagy. Consistent with in vitro results, data from the HCC-xenograft nude mouse model also indicated that combined treatment inhibited the mTOR pathway and promoted apoptosis and autophagy. In conclusion, epalrestat heightens sorafenib's anti-cancer effects via blocking the mTOR pathway, thus inducing cell cycle arrest, apoptosis, and autophagy.

Exploring the mechanisms underlying the therapeutic effect of the Radix Bupleuri-Rhizoma Cyperi herb pair on hepatocellular carcinoma using multilevel data integration and molecular docking

“…Most of these DEGs are involved in regulating cellular metabolism or cellular processes. Published studies have shown that DEGs, including MEP1A [ 28 ], AKR1B10 [ 29 ], CDK1 [ 30 ], and ADH1A [ 31 ], are involved in HCC growth. The liver is the main site of biotransformation, and its abnormal metabolism significantly alters the progression of liver cancer.…”

Predicting Non-Alcoholic Fatty Liver Disease Progression and Immune Deregulations by Specific Gene Expression Patterns

“…As storage of retinyl in cytoplasmic lipid droplets is the most distinctive feature of hepatic stellate cell (45), therefore, the abnormal expression of AKR1B10 may lead to the activation of HSC and promote the progression of NAFLD (46). Furthermore, studies have demonstrated that AKR1B10 was also related to tumor growth and metastasis, which may explain the lasting role in NAFL-NASH-HCC progression (47)(48)(49). Secreted phosphoprotein 1 (SPP1), also known as osteopontin (OPN), is a secreted glycoprotein that has multiple functions and affects proliferation, differentiation, migration and inflammation (50)(51)(52).…”

Regulation Network and Prognostic Significance of Aldo-Keto Reductase (AKR) Superfamily Genes in Hepatocellular Carcinoma

“…[34][35][36][37][38] For HCC, plenty of evidence has characterized the dysregulation of AKR1B10 in HCC. [39][40][41][42][43][44][45] In a large-scale proteome quantification of HCC, AKR1B10 was identified as a significantly dysregulated protein involved in HCC pathology. 46 Besides, as a secretory protein, AKR1B10 was also proposed and validated as a significant serum marker for HCC diagnosis in a large-scale multicenter study from China, which showed a better performance than traditional alphafetoprotein.…”