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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13046-016-0358-3) contains supplementary material, which is available to authorized users.