Abstract 2521: Inhibition of metabolic reprogramming by zerumbone alters the tumorigenic potential of hepatocellular cancer

Abstract

Abstract Incidence of hepatocellular carcinoma (HCC) that represents ~90% of all cases of primary liver cancer is on the rise worldwide. Sorafenib, the only approved targeted therapy, prolongs median survival only by ∼3 months. Thus, new therapeutic strategies are urgently needed. In this study, we investigated therapeutic potential of zerumbone, a sesquiterpene from an edible ginger, against HCC. Zerumbone inhibited proliferation and clonogenic survival of HCC cells by blocking glycolysis and pentose phosphate pathway, arresting cells at G2/M phase of cell cycle and inducing apoptosis. To uncover the underlying molecular mechanisms of its action on HCC cells, we employed several unbiased approaches. First, phosphokinase array showed significant inhibition PI3K/AKT/mTOR and STAT3 signaling in zerumbone-treated HCC cells. Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) of the microarray data revealed that zerumbone-deregulated genes showed positive correlation with PI3/AKT/mTOR and STAT3 pathways and those involved in metabolism, apoptosis and cell cycle. Notably, the alteration in expression of genes regulated by PI3/AKT/mTOR or STAT3 pathways and downregulated by zerumbone in HCCs is associated with poor patient survival. These results implicate that treatment with this dietary sesquiterpene might lead to a better outcome in HCC patients. Indeed, zerumbone treatment significantly inhibited growth and lung metastasis of orthotopic HCC xenografts in NSG mice. These findings reveal novel therapeutic strategies targeting cancer metabolism. Collectively, these observations underscore the therapeutic potential of zerumbone in HCC. Citation Format: Nissar A. Wani, Bo Zhang, Kun-yu Teng, Juan Barajas, Kalpana Ghoshal, Rafael Brüschweiler, Samson T. Jacob. Inhibition of metabolic reprogramming by zerumbone alters the tumorigenic potential of hepatocellular cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2521. doi:10.1158/1538-7445.AM2017-2521