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Mol Cancer Res. 2018 Feb;16(2):256-268. doi: 10.1158/1541-7786.MCR-17-0304. Epub 2017 Nov 29.

Reprograming of Glucose Metabolism by Zerumbone Suppresses Hepatocarcinogenesis.

Author information

1
Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.
2
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
3
Department of Chemistry & Biochemistry, The Ohio State University, Columbus, Ohio.
4
Department of Pathology, The Ohio State University, Columbus, Ohio.
5
Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio.
6
Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, Ohio.
7
Campus Chemical Instrument Center (CCIC) NMR, The Ohio State University, Columbus, Ohio.
8
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. kalpana.ghoshal@osumc.edu samson.jacob@osumc.edu.
9
Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio. kalpana.ghoshal@osumc.edu samson.jacob@osumc.edu.

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 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.

PMID:
29187559
PMCID:
PMC5805640
DOI:
10.1158/1541-7786.MCR-17-0304
[Indexed for MEDLINE]
Free PMC Article

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