Reprograming of Glucose Metabolism by Zerumbone Suppresses Hepatocarcinogenesis
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ABSTRACT:
PROVIDER: PRJNA418231 | ENA |
REPOSITORIES: ENA
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Project description:Hepatocellular carcinoma (HCC) is the most prevalent and highly aggressive liver malignancy with limited therapeutic options. Here, the therapeutic potential of zerumbone, a sesquiterpene derived from the ginger plant Zingiber zerumbet, against HCC was explored. Zerumbone inhibited proliferation and clonogenic survival of HCC cells in a dose-dependent manner by arresting cell at the G2/M phase, and inducing apoptosis. To elucidate the underlying molecular mechanisms, a phosphokinase array was performed that showed significant inhibition of the PI3K/AKT/mTOR and STAT3 signaling pathways in zerumbone treated HCC cells. Gene expression profiling using microarray and analysis of microarray data using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) revealed that zerumbone treatment resulted in significant deregulation of genes regulating apoptotic, cell cycle and metabolism. Indeed, tracing glucose metabolic pathways by growing HCC cells with 13C-glucose and measuring extracellular and intracellular metabolites by 2D-NMR showed a reduction in glucose consumption and reduced lactate production, suggesting glycolytic inhibition. Additionally, zerumbone impeded shunting of glucose-6-phosphate through the pentose-phosphate-pathway, thereby forcing tumor cells to undergo cell cycle arrest and apoptosis. Importantly, zerumbone treatment suppressed subcutaneous and orthotopic growth and lung metastasis of HCC xenografts in immune-compromised mice. In conclusion, these findings reveal a novel and potentially effective therapeutic strategy for HCC using a natural product that targets cancer cell metabolism.
2018-04-01 | GSE106855 | GEO
Project description:Hepatocellular carcinoma (HCC) is the most prevalent and highly aggressive liver malignancy with limited therapeutic options. Here, the therapeutic potential of zerumbone, a sesquiterpene derived from the ginger plant Zingiber zerumbet, against HCC was explored. Zerumbone inhibited proliferation and clonogenic survival of HCC cells in a dose-dependent manner by arresting cells at the G2-M phase and inducing apoptosis. To elucidate the underlying molecular mechanisms, a phosphokinase array was performed that showed significant inhibition of the PI3K/AKT/mTOR and STAT3 signaling pathways in zerumbone-treated HCC cells. Gene expression profiling using microarray and analysis of microarray data by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) revealed that zerumbone treatment resulted in significant deregulation of genes regulating apoptosis, cell cycle, and metabolism. Indeed, tracing glucose metabolic pathways by growing HCC cells with 13C6-glucose and measuring extracellular and intracellular metabolites by 2D nuclear magnetic resonance (NMR) spectroscopy showed a reduction in glucose consumption and reduced lactate production, suggesting glycolytic inhibition. In addition, zerumbone impeded shunting of glucose-6-phosphate through the pentose phosphate pathway, thereby forcing tumor cells to undergo cell-cycle arrest and apoptosis. Importantly, zerumbone treatment suppressed subcutaneous and orthotopic growth and lung metastasis of HCC xenografts in immunocompromised mice. In conclusion, these findings reveal a novel and potentially effective therapeutic strategy for HCC using a natural product that targets cancer cell metabolism.Implications: Dietary compounds, like zerumbone, that impact cell cycle, apoptosis, and metabolic processes may have therapeutic benefits for HCC patients. Mol Cancer Res; 16(2); 256-68. ©2017 AACR.
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Project description:Chronic jet lag induces spontaneous hepatocellular carcinoma (HCC) in wild-type mice following a mechanism very similar to that observed in obese humans. The process initiates with non-alcoholic fatty liver disease (NAFLD) that progresses to steatohepatitis and fibrosis before HCC detection. This pathophysiological pathway is driven by jet-lag-induced genome-wide gene deregulation and global liver metabolic dysfunction, with nuclear receptor-controlled cholesterol/bile acid and xenobiotic metabolism among the top deregulated pathways. Ablation of farnesoid X receptor dramatically increases enterohepatic bile acid levels and jet-lag-induced HCC, while loss of constitutive androstane receptor (CAR), a well-known liver tumor promoter that mediates toxic bile acid signaling, inhibits NAFLD-induced hepatocarcinogenesis. Circadian disruption activates CAR by promoting cholestasis, peripheral clock disruption, and sympathetic dysfunction.
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