Autophagy and liver cancer

Abstract

Autophagy is a highly conserved catabolic process that degrades cytosolic proteins and organelles via formation of autophagosomes that fuse with lysosomes to form autolysosomes, whereby autophagic cargos are degraded. Numerous studies have demonstrated that autophagy plays a critical role in the regulation of liver physiology and homeostasis, and impaired autophagy leads to the pathogenesis of various liver diseases such as viral hepatitis, alcohol associated liver diseases (AALD), non-alcoholic fatty liver diseases (NAFLD), and liver cancer. Recent evidence indicates that autophagy may play a dual role in liver cancer: inhibiting early tumor initiation while promoting progression and malignancy of already formed liver tumors. In this review, we summarized the progress of current understanding of how hepatic viral infection, alcohol consumption and diet-induced fatty liver diseases impair hepatic autophagy. We also discussed how impaired autophagy promotes liver tumorigenesis, and paradoxically how autophagy is required to promote the malignancy and progression of liver cancer. Understanding the molecular mechanisms underlying how autophagy differentially affects liver cancer development and progression may help to design better therapeutic strategies for prevention and treatment of liver cancer.

Keywords: Alcohol; Nrf2; TFEB; mTOR; p62.

Figure 1.

Regulation of autophagy by oncogenes and tumor suppressor genes. In the presence of insulin or growth factors, AKT is activated due to increased PI3K activity and binding with PDK1. AKT is negatively regulated by PTEN. Activated AKT phosphorylates TSC2 resulting in decreased TSC1-TSC2 complex activity leading to enhanced GTP-bound form of Rheb to stimulate mTORC1 activation. LKB1 phosphorylates and activates AMPK, and activated AMPK increased TSC2 phosphorylation on a different site of AKT resulting in increased TSC1-TSC2 complex activity which leads to decreased mTORC1 activation. Increased mTORC1 activity negatively regulates autophagy. PI3K, phosphatidylinositol 3-kinase; PDK1, phosphoinositide dependent kinase; AKT, protein kinase B; LKB1, serine-threonine kinase liver kinase B1; PTEN, phosphatase and tensin homolog; AMPK, AMP-activated protein kinase; TSC, tuberous sclerosis complex; RHEB, Ras homologue enriched in brain; mTOR, mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1.