Autophagy: A novel therapeutic target for hepatocarcinoma (Review)

Abstract

Autophagy is a highly conserved intracellular degradation process and plays an important role in hepatocarcinogenesis. Available data show that autophagy is involved in anti-hepatocarcinoma (HCC) therapies. Autophagy regulation involves a novel target for overcoming therapeutic resistance and sensitizing HCC to currently therapeutic methods. This is a systematic review on the interface of autophagy and the development of HCC and outlining the role of autophagy in current anti-HCC approaches. Understanding the significance of autophagy in anti-HCC therapy may offer a novel therapeutic target for improving anti-cancer efficacy and prolong survival for HCC patients.

Keywords: anti-hepatocarcinoma therapy; autophagy; hepatocarcinoma.

Figure 1

Autophagy is involved in the initiation of hepatocarcinoma (HCC). (A) Autophagy involvement in etiological factors of HCC. (a) Autophagy is induced by hepatitis B virus (HBV). Activating PI3K signal is one of the mechanisms in autophagy induced by HBV (25,26). (b) Autophagy is activated in hepatocytes infected with hepatitis C virus (HCV) through the activation of unfolded protein response signaling (27). (c) Autophagy is suppressed in obesity in hepatocytes possibly because the mTOR signaling pathway is overactivated by the metabolism of overnutrition (20). (d) Autophagy is inhibited by ethanol, which may be caused through the downregulation of AMPK activity (21). (B) A multi-stage process in the formation of HCC.

Figure 2

The dual role of autophagy in the development of hepatocarcinoma (HCC). Autophagy is activated as a response to stress, growth factors depletion, starvation and anti-tumor treatment. (A) Under autophagy-deficient conditions, cells succumb to death when challenged with death stimuli. Thus, autophagy acts as a tumor suppressor. On the other hand, proteins scavenged by autophagy accumulate and result in genetic instability, which in turn promote hepatocarcinogenesis. (B) Under autophagy-competent conditions, cells succumb to survival when challenged with death stimuli. Autophagy removes damaged organelles, misfolded and aggregated proteins, both of which generate free fatty acids and amino acids that can provide energy to facilitate hepatocarcinogenesis. However, the sustained activation of autophagy leads to autophagic cell death, termed as type II programmed cell death. FFA, free fatty acids.

Figure 3

Sorafenib activates autophagy through different signaling pathways. Autophagic cell death is triggered by sorafenib by suppressing myeloid cell leukemia-1 (Mcl-1)-related signaling pathway in hepatocarcinoma (HCC) PLC5, SK-Hep1, HepG2 and Hep3B cells (53). Thus, inducers of autophagy may be used in combination with sorafenib to promote anti-cancer efficacy. Cytoprotective autophagy is triggered by sorafenib through endoplasmic reticulum (ER) or the Akt/mTOR signaling pathway in MHCC97-L and PLC/PRF/5 cells (47,48). Inhibitors of autophagy may therefore be used in combination with sorafenib to promote anti-cancer efficacy.