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.
Project description:Chronic jet lag induces spontaneous hepatocellular carcinoma (HCC) in wild-type mice following a pathophysiological pathway very similar to that observed in obese humans. This process initiates with non-alcoholic fatty liver disease (NAFLD), progresses to steatohepatitis and fibrosis before HCC detection, and is driven by persistent genome-wide gene deregulation that induces global liver metabolic dysfunction. Nuclear receptor-controlled cholesterol/bile acid and xenobiotic metabolism are found among top deregulated pathways. Ablation of the bile acid receptor FXR dramatically increases intrahepatic bile acid levels and jet-lag-induced HCC, while loss of CAR, a well-known liver tumor promoter, inhibits NAFLD-induced hepatocarcinogenesis. Circadian disruption activates CAR by promoting cholestasis, peripheral clock disruption, and sympathetic dysfunction. Thus, FXR and CAR are clock-controlled therapeutic targets for spontaneous HCC
Project description:In this study transcriptome and lipidome profiling of triple negative breast cancer cells subjected to pharmacological inhibition of IRE1α revealed changes in lipid metabolism genes associated with an accumulation of triacylglycerols (TAGs). We identified DGAT2 mRNA, encoding the rate-limiting enzyme in TAG biosynthesis, as a RIDD target. Mechanistically, the DGAT2 transcript is cleaved by IRE1 at guanine 260 within a hairpin stem loop structure. Our results highlight the importance of IRE1 RIDD activity in reprograming cellular lipid metabolism
Project description:This study examines the relationship between sleep apnea and glucose metabolism. Physiological studies have demonstrated that 5 days of exposure to intermittent hypoxia (similar to what occurs with sleep apnea) leads to significant improvements in glucose tolerance. Therefore, this study investigates the hypothesis that intermittent hypoxia may lead to upregulation of some novel peptide(s) that have a powerful glucose lowering action. Keywords: other
Project description:Glucose-stimulated insulin secretion (GSIS) is suppressed through α-adrenergic receptor stimulation by catecholamines, epinephrine and norepinephrine, in pancreatic β-cells. Previous work has elucidated a bevy of adrenergic regulatory mechanisms beyond traditional Gi-coupled signaling including regulation of ion channels and interactions with exocytotic machinery. Glucose oxidation may also be an important site for adrenergic regulation of GSIS, but the link between epinephrine and glucose oxidation in β-cells is undefined. Here, we evaluate whether adrenergic stimulation decreases oxidative metabolism in β cells. Oxygen consumption rates were determined for Min6 and isolated rat islets in 20mM glucose complete media, then epinephrine was added at either 0 nM (vehicle control) or 100nM, followed by 10uM yohimbine (a selective Adrα2A antagonist). To identify glucose oxidation as the primary metabolic pathway affected by epinephrine, oxidation of 14C(U)-labeled glucose was determined in Min6 cells with epinephrine or vehicle. Oxygen consumption and glucose oxidation experiments were conducted in the presence of cAMP and insulin secretion blockers, respectively. Proteomics was performed on Min6 cells exposed to epinephrine for 4 hours and compared to controls. Epinephrine, but not vehicle, reduced (P<0.01) oxygen consumption rates in rat islets and Min6 cells to 64 ± 6% and 65 ± 1% of baseline, respectively, and yohimbine restored oxygen consumption to rates not different from baseline. In Min6 cells incubated with epinephrine rates of 14C glucose oxidation were reduced (P<0.01) 66 ± 4% compared to vehicle controls. These results demonstrate that acute epinephrine exposure suppresses glucose oxidation in β cells via the specific adrenergic receptor, Adrα2A, and indicate a new role for adrenergic regulation in GSIS.