Targeting autophagy in liver cancer

Abstract

Autophagy is a catabolic cellular process conserved in animals. It is characterized by the main role of recycling all the non-functional products of the cells. Once, autophagy players detect non-functioning sub-cellular organelles and proteins, they start the so-called nucleation process. The organelles will be surrounded by a double membrane vesicle mainly constituted by endoplasmic reticulum (ER) membrane and autophagy proteins, e.g., MAP1LC3B, Beclin-1, VPS34, Unc-51 like autophagy activating kinase (ULK1) and ubiquitination-related proteins. Then the autophagic membrane will go through an elongation phase involving additional autophagy players. Once the autophagic vesicle is complete, the sub-cellular organelles will be isolated from the rest of the cytosol and driven to the final fusion with lysosomes. Here, the digestion process will end. Alteration and or impairment of autophagy have been shown to be correlated with development of diseases affecting the central nervous system, e.g., Alzheimer and other neurodegenerative diseases. Nonetheless, autophagy defect is responsible for tumorigenesis in blood and solid malignancies, in particular liver cancer. Malignancies of the liver are determined by several genetics and epigenetics mechanisms triggering the up-regulation of survival mechanisms and resistance to cell death. Furthermore, liver cancer could result from pathologic conditions like cirrhosis and fibrosis related to virus infection, aflatoxin, alcohol consumption and high fat diet together with insulin resistance. The role exerted by autophagy in the pathogenesis of the liver and tumor development has been evidenced in recent years. The alteration of autophagy assumes a fundamental role for liver tumorigenesis determining an accumulation of non-functional proteins and organelles that trigger oxidative stress leading to genotoxic stress and gene alterations. Furthermore, the absence of this degradation mechanism could prompt the cells to alter their metabolic status and turn into malignant cells. Interestingly, the heterozygous loss of function of Beclin-1 is able to trigger liver tumorigenesis or even the simple accumulation of proteins caused by the block of the final autolysosome fusion and degradation process is responsible for liver cancer development. This review highlights the importance of targeting the autophagy process in liver cancer in order to restore its function and to promote autophagy-mediated cell demise.

A zinc finger family protein, ZNF263, promotes hepatocellular carcinoma resistance to apoptosis via activation of ER stress-dependent autophagy

“…Autophagy is a conserved intracellular process and plays an important role in preserving cellular homeostasis by degrading and recycling misfolded proteins and damaged organelles [ 11 ]. Autophagy is strongly induced upon environmental stresses and in most contexts promotes tumorigenesis [ 11 , 33 , 36 , 37 ]. Previous studies by us [ 14 , 33 , 38 ] and other groups [ 39 , 40 , 41 ] have demonstrated that cell autophagy is involved in HCC progression, which results in drug resistance and poor prognosis.…”

Autophagy: A Potential Therapeutic Target of Polyphenols in Hepatocellular Carcinoma

“…The significantly weaker tumor suppressor role of Atg4C needs further research to establish the key function of the autophagy mechanism in tumor suppression. Nonetheless, in hematological tumorigenesis and solid malignancies, particularly liver cancer, autophagy defects are observed [4]. The function of interferon-γ (IFN-γ) with proliferation inhibition on HCC has been shown by Li et al [83].…”

“…Autophagic aberrations cause oxidative stress, contributing to gene alterations, and could transform the cells to change their metabolism with the development of malignant cells. Autophagy, by contrast, acts as an anticancer mechanism, inhibiting the malignant transformation of normal cells into cancer cells [4]. In comparison, autophagy is also implicated in different stages of cancer development and metastasis.…”

A combination of AZD5363 and FH5363 induces lethal autophagy in transformed hepatocytes

“…An excessive stimulation of autophagy can be lethal for cancer cells either due to excess elimination of intracellular organelles and cytoplasmic content or activation of the Na + /K + ATPase pump to change membrane osmolality and ion transport 12,14 . Several studies suggested that treatment with some of the inhibitors results in induction of autophagy, leading to cell death of HCC 15,16 . The clinical lysosomotropic autophagy inhibitor chloroquine cooperates with the AKT inhibitor AZD5363 to inhibit autophagy, and sensitizes tumor cells to AZD5363-induced cell death in prostate cancer xenograft models, offering as a potential therapeutic approach in the clinic 17 .…”