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Reprograming of Glucose Metabolism by Zerumbone Suppresses Hepatocarcinogenesis

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106855 | GEO | 2018/04/01

REPOSITORIES: GEO

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Project description:Colitis is the common pathological lesion of inflammatory bowel diseases, the major chronic inflammatory diseases of intestinal tracts in humans. In this study, we investigated the therapeutic effects of ginger extract and its component zingerone in mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. Mice were administered with TNBS and/or various amounts of ginger and zingerone by an intrarectal route. The severity of colitis was evaluated by colonic weight/length ratio, macroscopic lesion, and histological examination. The mechanisms of ginger and zingerone were further elucidated by DNA microarray, ex vivo imaging, and immunohistochemical staining. Our data showed that treatment with ginger extract and zingerone ameliorated TNBS-induced colonic inflammation and injury in a dose-dependent manner. Pathway analysis of ginger- and zingerone-regulated gene expression profiles showed that ginger and zingerone significantly regulated cytokine-related pathways. Network analysis showed that nuclear factor-κB (NF-κB) and interleukin-1β (IL-1β) were key molecules involved in the expression of ginger- and zingerone-affected genes. Ex vivo imaging and immunohistochemical staining further verified that ginger and zingerone suppressed TNBS-induced NF-κB activation and decreased the NF-κB and IL-1β protein levels in the colon. In conclusion, our data showed that ginger improved the TNBS-induced colitis in mice via modulation of NF-κB activity and IL-1β signaling pathway. Moreover, zingerone might be the active component of ginger responsible for the amelioration of colitis induced by TNBS. A total of 24 mice was randomly divided into four groups of six mice: mock, mice were given with 0.1 ml of 50% ethanol; TNBS, mice were given with 250 mg/kg TNBS in 0.1 ml of 50% ethanol; TNBS/ginger, mice were administered with mixtures containing 250 mg/kg TNBS and various amounts of ginger extract in 0.1 ml of 50% ethanol; TNBS/zingerone, mice were given with mixtures containing 250 mg/kg TNBS and various amounts of zingerone in 0.1 ml of 50% ethanol. Mice were sacrificed seven days later for histochemical staining, RNA extraction, and ex vivo imaging.

Project description:Background: Tumor necrosis factor α-induced protein 1 (TNFAIP1) is frequently downregulated in cancer cell lines and promotes cancer cell apoptosis. However, its role, clinical significance and molecular mechanisms in hepatocellular carcinoma (HCC) are unknown. Methods: The expression of TNFAIP1 in HCC tumor tissues and cell lines was measured by Western blot and immunohistochemistry. The effects of TNFAIP1 on HCC proliferation, apoptosis, metastasis, angiogenesis and tumor formation were evaluated by Cell Counting Kit-8 (CCK8), Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL), transwell, tube formation assay in vitro and nude mice experiments in vivo. The interaction between TNFAIP1 and CSNK2B was validated by liquid chromatography-tandem mass spectrometry (LC-MS/MS), Co-immunoprecipitation and Western blot. The mechanism of how TNFAIP1 regulated nuclear factor-kappaB (NF-κB) pathway was analyzed by dual-luciferase reporter, immunofluorescence, quantitative Real-time polymerase chain reaction (RT-qPCR) and Western blot. Findings: The TNFAIP1 expression is significantly decreased in HCC tissues and cell lines, and negatively correlated with the increased HCC histological grade. Overexpression of TNFAIP1 inhibits HCC cell proliferation, metastasis, angiogenesis and promotes cancer cell apoptosis both in vitro and in vivo, whereas the knockdown of TNFAIP1 in HCC cell displays opposite effects. Mechanistically, TNFAIP1 interacts with CSNK2B and promotes its ubiquitin-mediated degradation with Cul3, causing attenuation of CSNK2B-dependent NF-κB trans-activation in HCC cell. Moreover, the enforced expression of CSNK2B counteracts the inhibitory effects of TNFAIP1 on HCC cell proliferation, migration, and angiogenesis in vitro and in vivo. Interpretation: Our results support that TNFAIP1 can act as a tumor suppressor of HCC by modulating TNFAIP1/CSNK2B/NF-κB pathway, implying that TNFAIP1 may represent a potential marker and a promising therapeutic target for HCC. Fund: This work was supported in part by the financial support from the China Natural Science Foundation (No. 81972642, No. 81601122 and No. 81770389), Hunan Natural Science Foundation (No. 2017JJ3205), Cooperative Innovation Center of Engineering and New Products for Developmental Biology of Hunan Province (No. 20134486), and the Scientific Research Fund of Hunan Provincial Education Department (17B162).

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Reprograming of Glucose Metabolism by Zerumbone Suppresses Hepatocarcinogenesis

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