Sorafenib-Induced Autophagy Promotes Glycolysis by Upregulating the p62/HDAC6/HSP90 Axis in Hepatocellular Carcinoma Cells.

Xiaoyu Yan,Wei Sun,Buhan Liu,Rui Tian,Xuesong Xu,Minghua Li,Jicheng Sun,Jing Su,Yuanxin Zhao

doi:10.3389/fphar.2021.788667

Abstract

Sorafenib has attracted much attention as the first drug approved by the FDA for the treatment of advanced hepatocellular carcinoma (HCC). Because of the drug tolerance, the overall outcomes were far from satisfactory. Current studies suggest that changes in glucose metabolism induced by sorafenib are the pivotal resistant mechanism of HCC cells, but the specific regulatory mechanism remains unclear, which makes it difficult to increase drug sensitivity by targeting glycolysis. As a metabolic-recycling pathway, autophagy regulates multiple important pathways involved in cell survival and death. In this study, we found the expression of key autophagy proteins were closely related to the prognosis and progression of HCC patients. Based on in vitro experiments, our studies showed sorafenib induced autophagy in HCC cells. Inhibition of autophagy by chloroquine could significantly increase the sensitivity of HCC cells to sorafenib and reverse the enhancement of glycolysis. Furthermore, sorafenib-induced autophagy promoted the deacetylase activity of HDAC6 by degrading p62, which promoted the activity of PKM2 by regulating the acetylation of its critical substrate HSP90. In this study, we investigated the role of autophagy-induced HDAC6 in regulating the key glycolytic enzyme PKM2, which may be helpful to clarify the relationship between autophagy and glycolysis in a sorafenib-resistant mechanism. Targeting p62/HDAC6/HSP90 could herald a potential improvement in HCC therapy.

Highlights

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors
This study used the key autophagy receptor protein p62 and autophagosome membrane protein LC3 to determine the autophagy level of hepatocellular carcinoma (HCC) cells; low expression of p62 and high expression of LC3 are indicative of a smooth autophagy flux, and accumulation of p62 and LC3 in the cell indicates the blockage of autophagosome clearance (Jiang and Mizushima, 2015)
These results suggested that autophagy level was associated with poor prognosis and progression of HCC patients

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors. No systematic treatment has been clearly proved to improve the survival rate of patients with advanced HCC. Sorafenib has attracted substantial attention as the first drug approved by the United States Food and Drug Administration for the treatment of advanced HCC (Llovet et al, 2008). It is believed that targeting the kinase activity in the Ras/Raf/MEK/ERK signaling, platelet-derived growth factor receptor (PDGFR-β) and vascular endothelial growth factor receptor (VEGFR) all contributed to its roles in tumor suppression (Fan et al, 2020). Sorafenib-Induced Autophagy Promotes Glycolysis outcomes were far from satisfactory. A growing body of evidence supporting energy metabolism, autophagy ATP binding box (ABC) transporters non-coding RNAs, and hypoxic microenvironment were involved in the resistant mechanism (Méndez-Blanco et al, 2019; Tang et al, 2020)

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