Abstract
Lipid metabolism that correlates tightly to the glucose metabolic regulation in malignant cells includes hepatocellular carcinoma (HCC) cells. The transcription factor Sterol Regulatory Element Binding Protein 1 (SREBP-1), a regulator of fatty acid synthesis, has been shown to pivotally regulate the proliferation and metastasis of HCC cells. However, the intrinsic mechanism by which SREBP-1 regulates the survival of HCC cells remains unclear. In this study, among HCC patients who had dismal responses to Sorafenib, a high SREBP-1 level was found in the tumors and correlated to poor survival. This observation suggested the negative role of SREBP-1 in clinical HCC prognosis. Our mechanistical studies reveal that the inhibition of SREBP-1 via its inhibitor Betulin suppresses cellular glucose metabolism. In addition to the reduced glycolytic activity, a thwarted metastatic potential was observed in HCC cells upon Betulin administration. Moreover, our data show that SREBP-1 inhibition facilitated the antitumor effects of Sorafenib on HCC cells and xenograft tumors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / toxicity
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / mortality
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Carcinoma, Hepatocellular / pathology
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Cell Movement / drug effects
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Cell Movement / genetics
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Drug Synergism
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Glycolysis / drug effects*
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Glycolysis / genetics
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Hep G2 Cells
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Humans
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Lipid Metabolism / drug effects
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Lipid Metabolism / genetics
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / metabolism
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Liver Neoplasms / mortality
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Liver Neoplasms / pathology
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Mice
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Mice, Nude
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Prognosis
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Sorafenib / pharmacology*
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Sorafenib / therapeutic use
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Sterol Regulatory Element Binding Protein 1 / antagonists & inhibitors
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Sterol Regulatory Element Binding Protein 1 / genetics
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Sterol Regulatory Element Binding Protein 1 / metabolism*
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Transplantation, Heterologous
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Triterpenes / pharmacology*
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Triterpenes / therapeutic use
Substances
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SREBF1 protein, human
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Sterol Regulatory Element Binding Protein 1
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Triterpenes
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betulin
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Sorafenib