Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma

Abstract

Liver cancer has become the sixth most diagnosed cancer and the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is responsible for up to 75-85% of primary liver cancers, and sorafenib is the first targeted drug for advanced HCC treatment. However, sorafenib resistance is common because of the resultant enhancement of aerobic glycolysis and other molecular mechanisms. Aerobic glycolysis was firstly found in HCC, acts as a hallmark of liver cancer and is responsible for the regulation of proliferation, immune evasion, invasion, metastasis, angiogenesis, and drug resistance in HCC. The three rate-limiting enzymes in the glycolytic pathway, including hexokinase 2 (HK2), phosphofructokinase 1 (PFK1), and pyruvate kinases type M2 (PKM2) play an important role in the regulation of aerobic glycolysis in HCC and can be regulated by many mechanisms, such as the AMPK, PI3K/Akt pathway, HIF-1α, c-Myc and noncoding RNAs. Because of the importance of aerobic glycolysis in the progression of HCC, targeting key factors in its pathway such as the inhibition of HK2, PFK or PKM2, represent potential new therapeutic approaches for the treatment of HCC.

Keywords: Aerobic glycolysis; HIF-1α; HK2; Hepatocellular carcinoma; PFK1; PKM2.

Fig. 1

Aerobic glycolysis process and its three rate-limiting enzymes. Aerobic glycolysis was originally found in HCC and is the process that converts glucose into pyruvate and lactate instead of using OXPHOS even in sufficient O₂ supply. HK2, PFK1 and PKM2 are the three rate-limiting enzymes involved in glycolysis. HK2 catalyzes glucose to G-6-P, and can interact and bind with VDAC1 in the mitochondrial outer membrane to facilitate the production of ATP and the inhibition of apoptosis. PFK1 can catalyze F-6-P to F-1,6-BP, and its activity can be regulated by PFKFB3 catalyzed products F-2,6-BP. PKM2 not only catalyzes PEP to pyruvate, but can also translocate into the nucleus and act as a co-activator for some transcription factors, such as HIF-1α, β-catenin/c-Myc, NF-κB and STAT3, to promote the transcription of relevant target genes

Fig. 2

The activity of PKM2 is dependent upon its oligomerization states. The PKM2 tetramer exhibits high levels of pyruvate kinase activity and can accelerate the transformation of PEP to pyruvate, thereby increasing the glycolytic flux and ATP production rates. Whereas PKM2 in dimeric form exhibits lower levels of pyruvate kinase activity, and can be phosphorylated at Tyr105, Tyr 328, Thr328 or Pro403/408 sites and then translocate into nucleus to act as a co-activator for some transcription factors, such as HIF-1α, β-catenin/c-Myc, NF-κB and STAT3, leading to tumor progression

Fig. 3

Regulatory mechanisms involved in aerobic glycolysis in HCC. Aerobic glycolysis can be regulated by various transcriptional factors, such as HIF-1α and c-Myc, and many signaling pathways, such as AMPK and PI3K/Akt, as well as noncoding RNAs. The regulatory mechanisms include the regulation of enzymes activity and the relative gene expression levels, and both mechanisms are tightly intertwined