Abstract
Glycolysis inhibitors are promising therapeutic drugs for tumor treatment, which target the uniquely elevated glucose metabolism of cancer cells. Butyrate is a critical product of beneficial microbes in the colon, which exerts extraordinary anti-cancer activities. In particular, butyrate shows biased inhibitory effects on the cell growth of cancerous colonocytes, whereas it is the major energy source for normal colonocytes. Besides its roles as the histone deacetylases (HDACs) inhibitor and the ligand for G-protein coupled receptor (GPR) 109a, the influence of butyrate on the glucose metabolism of cancerous colonocytes and the underlying molecular mechanism are not fully understood. Here, we show that butyrate markedly inhibited glucose transport and glycolysis of colorectal cancer cells, through reducing the abundance of membrane GLUT1 and cytoplasmic G6PD, which was regulated by the GPR109a-AKT signaling pathway. Moreover, butyrate significantly promoted the chemotherapeutical efficacy of 5-fluorouracil (5-FU) on cancerous colonocytes, with exacerbated impairment of DNA synthesis efficiency. Our findings provide useful information to better understand the molecular basis for the impact of butyrate on the glucose metabolism of colorectal cancer cells, which would promote the development of beneficial metabolites of gut microbiota as therapeutical or adjuvant anti-cancer drugs.
Highlights
Inhibition of glycolysis in cancer cells is an emerging and powerful approach to combat cancer (Hay, 2016)
In order to identify the specific glucose transporter sensitive to butyrate in colorectal cancer cells, expression levels of Glucose transporter 1-5 (GLUT1-5) in HCT116 and LoVo cell lines being treated with PBS or butyrate for 24 h were compared
In comparison to cells treated with only butyrate, treatment with both butyrate and SC79 increased the membrane content of GLUT1 by five times and 3.5 times in HCT116 and LoVo cells, respectively (Figure 2D). These results demonstrated that the inhibitory effect of butyrate on the membrane content of GLUT1 and glucose uptake efficiency in colorectal cancers cells was restored by an AKT phosphorylation activating bioreagent, indicating that AKT pathway is essential for butyrate to inhibit glucose uptake of colorectal cancer cells
Summary
Inhibition of glycolysis in cancer cells is an emerging and powerful approach to combat cancer (Hay, 2016). Butyrate has been identified as a ligand for G protein-coupled receptor 109a (GPR109a) in cancerous cells, which regulates tumor growth by activating the downstream signal cascade of GPR109a (Thangaraju et al, 2009). The WNT signaling pathway, which is able to modulate the expression of various oncogenes, could be suppressed by the activation of GPR109a by butyrate, leading to the impairment of tumor growth (Chen et al, 2020). Besides revealing its role in activating the GPR109a mediated signaling pathway and acting as the HDACs inhibitor (Koh et al, 2016), its influence on the glucose metabolism of cancerous colonocytes and the underlying molecular mechanism are not fully explored
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