FLIPL is critical for aerobic glycolysis in hepatocellular carcinomaReport as inadecuate

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Journal of Experimental and Clinical Cancer Research

, 35:79

First Online: 13 May 2016Received: 28 March 2016Accepted: 06 May 2016DOI: 10.1186-s13046-016-0358-3

Cite this article as: Lei, S., Yang, J., Chen, C. et al. J Exp Clin Cancer Res 2016 35: 79. doi:10.1186-s13046-016-0358-3


BackgroundTumor 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.

MethodsThe effects of FLIPL the long form of FLIP on aerobic glycolysis and glucose uptake were assessed in HCC cells and xenograft tumors. The correlations between FLIPL expression and sodium-glucose cotransporter 1 SGLT1 expression in clinical HCC tissues were analyzed. The consequences of FLIPL-induced regulation of SGLT1 at the transcription and translation levels and the interaction between FLIPL and SGLT1 were examined. FLIPL-mediated tolerance upon glucose limitation and its mechanism were detected.

ResultsWe report a novel role for FLIPL in promoting the aerobic glycolysis of HCC cells. FLIPL overexpression induced a significant increase in cell aerobic glycolysis indexes including glucose uptake, glucose consumption, and lactate production. FLIPL co-localized and interacted with SGLT1, a major active glucose transporter in HCC cells. FLIPL increased the stability of SGLT1 protein by inhibiting its ubiquitination and degradation. The expression level of FLIPL was positively correlated with the expression level of SGLT1 in 79 HCC tissues from surgical operation. Furthermore, FLIPL increased cell tolerance ability and decreased cell apoptosis to low glucose by regulating SGLT1.

ConclusionsOur results indicate that FLIPL plays an essential role in HCC aerobic glycolysis and that SGLT1 is required for FLIPL-modulated tumor proliferation under low glucose conditions. Targeting the actions of FLIPL in cell glucose-dependent aerobic glycolysis may provide an attractive strategy for therapeutic intervention in HCC.

KeywordsHepatocellular carcinoma Cellular FLICE-like inhibitory protein Sodium-glucose cotransporter 1 Aerobic glycolysis Glucose uptake Electronic supplementary materialThe online version of this article doi:10.1186-s13046-016-0358-3 contains supplementary material, which is available to authorized users.

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Author: Shixiong Lei - Jiandong Yang - Chong Chen - Jiachen Sun - Liu Yang - Haili Tang - Tao Yang - An Chen - Huadong Zhao - Yan

Source: https://link.springer.com/

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