The treatment for advanced primary hepatocellular carcinoma (HCC) is sorafenib (SORA), while HCC has become increasingly drug resistant with enhanced aerobic glycolysis. The present study aimed to examine the chemotherapeutic effects of a flavonoid proanthocyanidin B2 (PB2) on HCC. Five kinds of HCC cell lines and LO2 were used to test the effect of PB2 on aerobic glycolysis. The proliferation, cell cycle, apoptosis and a xenograft mouse model were analyzed. Lentivirus overexpressed pyruvate kinase M2 (PKM2) or sh-PKM2 was used to verify the target of PB2. The detailed mechanism was investigated by immunofluorescence, co-immunoprecipitation, and western blotting. PB2 inhibited the proliferation, induced cell cycle arrest, and triggered apoptosis of HCC cells in vivo and in vitro. PB2 also suppressed glucose uptake and lactate levels via the direct inhibition of the key glycolytic enzyme, PKM2. In addition, PKM2 inhibited the nuclear translocation of PKM2 and co-localization of PKM2/HIF-1α in the nucleus, leading to the inhibition of aerobic glycolysis. Co-treatment with PB2 was also effective in enhancing the chemosensitivity of SORA. PB2 inhibited the expression and nuclear translocation of PKM2, therefore disrupting the interaction between PKM2/HSP90/HIF-1α, to suppress aerobic glycolysis and proliferation, and trigger apoptosis in HCC via HIF-1α-mediated transcription suppression.

Objective: Shikonin is a natural product with many activities, including anti-cancer effects. Pyruvate kinase type M2 (PKM2) plays a crucial role in the growth of tumor cells. However, the effect of shikonin on PKM2 in hepatocellular carcinoma (HCC) is unclear. Methods: Cell viability, apoptosis level, glucose uptake, and lactate production were detected in HCC cells. Lentivirus-overexpressed and –shRNA of PKM2 were used to verify the key target of shikonin. A xenograft mouse model was used to detect the efficacy of shikonin and its combination with sorafenib in vivo. Results: Shikonin inhibited proliferation and glycolysis and induced apoptosis in HCC cells. Either PKM2-overexpressed or PKM2-shRNA alleviated or enhanced this effect. The results of CCK-8 showed that shikonin significantly inhibited cell viability of HCC cells. The levels of glucose uptake and lactate production were dramatically decreased by shikonin-treated. Results of flow cytometry and Western blot showed that the levels of apoptosis of HCC cells were significantly increased in a dose-dependent manner after shikonin treatment. In addition, shikonin enhanced the anti-cancer effect of sorafenib in vitro and in vivo. Our results showed that SK combined with sorafenib markedly inhibits tumor growth in HCC-transplanted nude mice compared to SK or sorafenib alone. Conclusion: By inhibiting PKM2, shikonin inhibited proliferation and glycolysis and induced cell apoptosis in HCC cells. The effect of shikonin on tumor cell proliferation, apoptosis and glycolsis will make it promising drug for HCC patients.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. HCC incidence rate is sixth and mortality is fourth worldwide. However, HCC pathogenesis and molecular mechanisms remain unclear. The incidence of HCC is associated with genetic, environmental, and metabolic factors. The role of gut microbiota in the pathogenesis of HCC has attracted researchers’ attention because of anatomical and functional interactions between liver and intestine. Studies have demonstrated the involvement of gut microbiota in the development of HCC and chronic liver diseases, such as alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and liver cirrhosis. Peroxisome proliferator-activated receptors (PPARs) are a group of receptors with diverse biological functions. Natural and synthetic PPAR agonists show potential for treatment of NAFLD, liver fibrosis, and HCC. Recent studies have demonstrated that PPARs take part in gut microbiota inhabitation and adaptation. This manuscript reviews the role of gut microbiota in the development of HCC and precancerous diseases, the role of PPARs in modulation of gut microbiota and HCC, and potential of gut microbiota for HCC diagnosis and treatment.

Hepatic ischemia and reperfusion injury is characterized by hepatocyte apoptosis, impaired autophagy, and oxidative stress. Fenofibrate, a commonly used antilipidemic drug, has been verified to exert hepatic protective effects in other cells and animal models. The purpose of this study was to identify the function of fenofibrate on mouse hepatic IR injury and discuss the possible mechanisms. A segmental (70) hepatic warm ischemia model was established in Balb/c mice. Serum and liver tissue samples were collected for detecting pathological changes at 2, 8, and 24h after reperfusion, while fenofibrate (50mg/kg, 100mg/kg) was injected intraperitoneally 1 hour prior to surgery. Compared to the IR group, pretreatment of FF could reduce the inflammatory response and inhibit apoptosis and autophagy. Furthermore, fenofibrate can activate PPAR-α, which is associated with the phosphorylation of AMPK.