Abstract B12: Analysis of Lipid Metabolism and Gene Expression in Hepatocellular Carcinoma Reveals Mitochondrial Function as a Potential Target for Combinatorial Treatment

Abstract

Abstract Background: Hepatocellular carcinoma (HCC), the most common malignant liver tumor, is a heterogeneous disease with little efficacious chemotherapy. Lipid metabolic dysfunction is integral to the pathogenesis of HCC, but the underlying mechanisms remain poorly understood. HCC cell lines and patient tumors can be classified into hepatocyte and hepatoblast subtypes based on gene expression patterns, with the hepatoblast type being more aggressive. Methods: We characterized the RNA expression profiles of 20 HCC cell lines (13 hepatoblast and 7 hepatocyte type) and 1 normal immortalized liver cell line. We also characterized the steady state concentrations of hundred of metabolites of these cells lines. In addition, to find the specific small molecules to inhibit their growth we tested a panel of metabolic pathway inhibitors for activity against these cell lines. Results: There are significant differences between the transcriptional profiles of the two subtypes of HCC, as well as between HCC cell lines and the normal liver cell line. The most important determinants of these differences are in lipid metabolic pathways. Analysis of the microarray data, corroborated by real time quantitative PCR analysis showed significant difference between transcript levels of ACOX1, ACOX2, FASN, SCD1, and SCAP, as well as in fatty acid transport proteins (FATPs, SLC27As) and elongation enzymes (ELOVL). Metabolomic studies show that not only are there differences between the steady state amounts of long chain and very long chain fatty acids among the groups, but there are also differences in the levels of acyl-carnitines. These differences indicate that there is variability in their reliance on mitochondrial oxidative respiration. Accordingly, there are significant differences between the sensitivity of the HCC cell lines to oligomycin compared with a normal liver cell line. Conclusion: These data point to the importance of lipid metabolic and mitochondrial oxidative dysfunction in the pathogenesis of hepatocellular carcinoma. We anticipate combining the inhibition of oxidative phosphorylation with the standard of care treatment consisting of sorafenib to allow for a much lower and better tolerated dose of both drugs while maintaining anti-tumor efficacy. Citation Format: Ali Zarrinpar, Tiziana Palumbo, Dinesh Barupal. Analysis of Lipid Metabolism and Gene Expression in Hepatocellular Carcinoma Reveals Mitochondrial Function as a Potential Target for Combinatorial Treatment [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B12.