FLIP L is critical for aerobic glycolysis in hepatocellular carcinoma

Background Tumor cells use aerobic glycolysis to rapidly generate ATP and growth substrate which expenses a large amount of glucose. However, how tumor cells take in enough glucose from the tumor microenvironment of insufficient blood supply remains poorly understood. The cellular FLICE-like inhibitory protein (FLIP), a cell apoptosis inhibiting molecule, is highly expressed in hepatocellular carcinoma (HCC) and is implicated in HCC development. Methods The effects of FLIP L (the long form of FLIP) on aerobic glycolysis and glucose uptake were assessed in HCC cells and xenograft tumors. The correlations between FLIP L expression and sodium/glucose cotransporter 1 (SGLT1) expression in clinical HCC tissues were analyzed. The consequences of FLIP L -induced regulation of SGLT1 at the transcription and translation levels and the interaction between FLIP L and SGLT1 were examined. FLIP L -mediated tolerance upon glucose limitation and its mechanism were detected. Results We report a novel role for FLIP L in promoting the aerobic glycolysis of HCC cells. FLIP L overexpression induced a significant increase in cell aerobic glycolysis indexes including glucose uptake, glucose consumption, and lactate production. FLIP L co-localized and interacted with SGLT1, a major active glucose transporter in HCC cells. FLIP L increased the stability of SGLT1 protein by inhibiting its ubiquitination and degradation. The expression level of FLIP L was positively correlated with the expression level of SGLT1 in 79 HCC tissues from surgical operation. Furthermore, FLIP L increased cell tolerance ability and decreased cell apoptosis to low glucose by regulating SGLT1. Conclusions Our results indicate that FLIP L plays an essential role in HCC aerobic glycolysis and that SGLT1 is required for FLIP L -modulated tumor proliferation under low glucose conditions. Targeting the actions of FLIP L in cell glucose-dependent aerobic glycolysis may provide an attractive strategy for therapeutic intervention in HCC.