Sodium butyrate inhibits aerobic glycolysis of hepatocellular carcinoma cells via the c‐myc/hexokinase 2 pathway

Abstract

Aerobic glycolysis is a well-known hallmark of hepatocellular carcinoma (HCC). Hence, targeting the key enzymes of this pathway is considered a novel approach to HCC treatment. The effects of sodium butyrate (NaBu), a sodium salt of the short-chain fatty acid butyrate, on aerobic glycolysis in HCC cells and the underlying mechanism are unknown. In the present study, data obtained from cell lines with mouse xenograft model revealed that NaBu inhibited aerobic glycolysis in the HCC cells in vivo and in vitro. NaBu induced apoptosis while inhibiting the proliferation of the HCC cells in vivo and in vitro. Furthermore, the compound inhibited the release of lactate and glucose consumption in the HCC cells in vitro and inhibited the production of lactate in vivo. The modulatory effects of NaBu on glycolysis, proliferation and apoptosis were related to its modulation of hexokinase 2 (HK2). NaBu downregulated HK2 expression via c-myc signalling. The upregulation of glycolysis in the HCC cells induced by sorafenib was impeded by NaBu, thereby enhancing the anti-HCC effect of sorafenib in vitro and in vivo. Thus, NaBu inhibits the expression of HK2 to downregulate aerobic glycolysis and the proliferation of HCC cells and induces their apoptosis via the c-myc pathway.

A novel cuproptosis-related prognostic signature and potential value in HCC immunotherapy

“…Pericyte-hexokinase 2 (HK2) is the key rate-limiting enzyme of the glycolytic pathway, which is associated with pathological stage and prognosis ( DeWaal et al, 2018 ). In the mouse model of HCC, HK2 silencing could synergistically enhance the sensitivity of HCC cells to sorafenib ( Yu et al, 2022 ). CYP26 enzymes are the major enzymes responsible for the clearance of retinoic acid (RA), which is an important endogenous signaling molecule that regulates the cell cycle and maintains epithelial cells.…”

A pan-cancer analysis of the role of hexokinase II (HK2) in human tumors

“…Recently, a fifth hexokinase, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in liver cancer compared to healthy liver tissue 26 . Studies revealed that inhibiting HK2-mediated glycolysis can enhance the anti-hepatocellular carcinoma activity of sorafenib 27 , 28 . HK2 may be a possible therapeutic target for liver cancer.…”

Research progress of abnormal lactate metabolism and lactate modification in immunotherapy of hepatocellular carcinoma

“…MACC1 and STAT3 also enhance glucose metabolism and lactate production through HK2 (41,42). Blockade of FOXK1, EGFR, C-MYC signaling inhibits HK2-mediated glycolysis (42)(43)(44). Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been considered as a stably expressed reference gene in the past, and GAPDH has been reported to be up-regulated in various cancers (45).…”