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.
Highlights
According to the latest global cancer statistics (2018), liver cancer has become the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide in 2018 [1]
pyruvate kinases type M2 (PKM2) can promote the transcription of target genes, such as hypoxia inducible factor-1α (HIF-1α) targeted expression of GLUTs, PKM2, LDH-A, and vascular endothelial growth factor (VEGF)-A, leading to the promotion of growth, positive feedback regulated-glycolysis and angiogenesis in cancer cells [63]
Heterogeneous ribonucleoprotein influences the alternative splicing of PKM genes, giving rise to differences in the PKM1/PKM2 ratio [70]. Some signaling pathways, such as HIF-1α, phosphoinositide 3-kinases (PI3Ks)/mammalian target of rapamycin (mTOR) and PPAR-γ, upregulate the expression of PKM2 to promote the growth of cancer cells [71]
Summary
According to the latest global cancer statistics (2018), liver cancer has become the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide in 2018 [1]. PKM2 can promote the transcription of target genes, such as HIF-1α targeted expression of GLUTs, PKM2, LDH-A, and VEGF-A, leading to the promotion of growth, positive feedback regulated-glycolysis and angiogenesis in cancer cells [63]. Some signaling pathways, such as HIF-1α, PI3K/mTOR and PPAR-γ, upregulate the expression of PKM2 to promote the growth of cancer cells [71].
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