Will AMPK be a potential therapeutic target for hepatocellular carcinoma?

Abstract

Cancer is the disease that poses the greatest threat to human health today. Among them, hepatocellular carcinoma (HCC) is particularly prominent due to its high recurrence rate and extremely low five-year postoperative survival rate. In addition to surgical treatment, radiotherapy, chemotherapy, and immunotherapy are the main methods for treating HCC. Due to the natural drug resistance of chemoradiotherapy and targeted drugs, satisfactory results have not been achieved in terms of therapeutic efficacy and cost. AMP-Activated Protein Kinase (AMPK) is a serine/threonine protein kinase. It mainly coordinates the metabolism and transformation of energy between cells, which maintaining a balance between energy supply and demand. The processes of cell growth, proliferation, autophagy, and survival all involve various reaction of cells to energy changes. The regulatory role of AMPK in cellular energy metabolism plays an important role in the occurrence, development, treatment, and prognosis of HCC. Here, we reviewed the latest progress on the regulatory role of AMPK in the occurrence and development of HCC. Firstly, the molecular structure and activation mechanism of AMPK were introduced. Secondly, the emerging regulator related to AMPK and tumors were elaborated. Next, the multitasking roles of AMPK in the occurrence and development mechanism of HCC were discussed separately. Finally, the translational implications and the challenges of AMPK-targeted therapies for HCC treatment were elaborated. In summary, these pieces of information suggest that AMPK can serve as a promising specific therapeutic target for the treatment of HCC.

Keywords: AMPK; Hepatocellular carcinoma; challenges and limitations; multitasking roles; regulator.

Figure 1

The overall molecular structure of AMPK. AMPK is composed of α, β and γ subunits. The α subunit plays a catalytic role, β and γ play a regulatory role. Each of the subunits has 2/3 isoforms encoded by genes (α1 and α2; β1 and β2; γ1, γ2 and γ3). The subunit α contains 548 amino acids, which can be divided into a N-terminal of the catalytic domain, an intermediate auto-inhibitory domain, and a C-terminal of the subunit binding domain. The N-terminus is the core site of catalysis, containing a typical catalytic domain of serine/threonine protein kinase. The self-inhibitory domain can reduce AMPK activity at low levels of AMP. The subunit β is like a bracket of α and γ subunits, which can connect α and γ subunits together. The subunit γ can be referred to as regulatory subunit, which can bind to regulatory substances such as ATP, AMP, or ADP.

Figure 2

Several specific activators of AMPK related to tumors (A) and its IUPAC name of the compound (B).

Figure 3

Schematic diagram of the multitasking roles of AMPK in regulating the progression of HCC.