Abstract
Hepatocellular carcinoma (HCC) accounts for approximately 90% of all cases of primary liver cancer; it is the third most frequent cause of cancer-related death worldwide. In early-stage disease, surgical resection and liver transplantation are considered curative treatments. However, the majority of HCC patients present with advanced-stage disease that is treated using palliative systemic therapy. Since HCC is heterogeneous owing to its multiple etiologies, various risk factors, and inherent resistance to chemotherapy, the development of an effective systemic treatment strategy for HCC remains a considerable challenge. Autophagy is a lysosome-dependent catabolic degradation pathway that is essential for maintaining cellular energy homeostasis. Autophagy dysfunction is closely linked with the pathogenesis of various cancers; therefore, the discovery of small molecules that can modulate autophagy has attracted considerable interest in the development of a systemic treatment strategy for advanced HCC. Here, we reviewed the roles of autophagy in HCC and the recent advances regarding small molecules that target autophagy regulatory mechanisms.
Highlights
Hepatocellular carcinoma (HCC) is a malignant tumor with a high recurrence rate and poor prognosis
A series of protein complexes composed of autophagy-related gene (ATG) products coordinates the autophagy process that consists of initiation, nucleation, elongation, maturation, fusion, and degradation (Figure 1)
We found that DC promoted autophagic cell death and necrosis; the stimulation of endoplasmic reticulum (ER) stress by DC induced autophagy via p62 transcriptional activation involving an ER stress sensor, the inositol-requiring enzyme 1 (IRE1)/Jun N-terminal kinase (JNK) pathway [67]
Summary
Hepatocellular carcinoma (HCC) is a malignant tumor with a high recurrence rate and poor prognosis. It is the third leading cause of cancer-related death worldwide [1]. Systemic therapy (with sorafenib, a multityrosine kinase inhibitor) is a critical therapeutic strategy for patients with advanced-stage HCC, but the overall median survival is less than 3 months [5]. Autophagy is a highly conserved lysosome-dependent intracellular degradation process. It plays a critical role in maintaining cellular homeostasis [9]. Emerging evidence indicates that autophagy dysregulation is linked to the pathogenesis of liver diseases such as NASH, fibrosis, cirrhosis, and HCC [12]. Here, we review recent advances regarding the discovery of small molecules that can target the various regulatory mechanisms of autophagic machinery and highlight the potential therapeutic applications of these compounds in HCC
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