ORIGINAL PAPER NFκB activation demarcates a subset of hepatocellular carcinoma patients for targeted therapy Vignesh Ramesh 1 & Karthikeyan Selvarasu 1 & Jaishree Pandian 1 & Soundarajan Myilsamy 1 & Chidambaranathan Shanmugasundaram 1 & Kumaresan Ganesan 1 Accepted: 10 August 2016 # International Society for Cellular Oncology 2016 Abstract Background Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide. It is a heterogeneous disorder and >80 % of the tumors develop in patients with liver cirrhosis, resulting from chronic inflammation and/or fibrosis. Here, we set out to identify novel targets for HCC therapy and to define a sub- group of patients that might benefit most from it. Methods Cellular pathway activation profiling of 45 tran- scription factors in a HCC-derived cell line (HEP3B), in vitro analysis of NFκB reporter activity in additional HCC-derived cell lines and pathway-focused integrative anal- yses of publicly available primary HCC-derived expression profiling data (GSE6764, GSE9843, E-TABM-36 and E- TABM-292) were employed to reveal a role of NFκB in HCC development. In order to identify potential targeting agents, a luciferase-based NFκB reporter screening assay was established in HEP3B cells. After screening of a drug library through this assay, a potent NFκB pathway inhibitor was identified and characterized using an array of additional in vitro assays. Results Using cellular pathway activation profiling, we found a high activation of NFκB-mediated signaling in HCC- derived cell lines and in primary HCC tumors. Through NFκB inhibitor screening we observed a highly efficacious NFκB pathway inhibitory potential of ornithogalum in HCC-derived HEP3B cells. Although its active component still remains to be defined, ornithogalum has been found to inhibit endoplasmic reticulum (ER) and oxidative stress re- sponses. ER stress, oxidative stress and NFκB signaling were found to be enhanced in a subset of HCCs, as well as in (precancerous) liver cirrhosis tissues. Conclusion From our data we conclude that NFκB signaling is activated in precancerous cirrhosis tissues and in a subset of HCCs. We found that ornithogalum exhibits NFκB targeting and stress relieving activities. NFκB inhibitors, including the active component of ornithogalum, may serve as putative pre- ventive and targeted therapeutic agents for at least a subset of HCCs in which the NFκB pathway is activated. These latter notions require further investigation in a translational context. Keywords Hepatocellular carcinoma . NFkB pathway . Targeted therapy . Ornithogalum . ER stress . Oxidative stress . Anti-inflammatory 1 Introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death worldwide [1]. Liver stress such as inflammation and its associated liver damage may result in liver cirrhosis and/or fibrosis, dysplastic lesions and, ultimately, invasive liver cancer [2]. Genome- wide analyses have revealed a heterogeneous nature of HCC [3, 4] and a concomitant de-regulation of different signaling pathways, including the JAK/STAT, ERK/MAPK, PI3K/AKT, Wnt, Hedgehog and NFκB pathways [5–8]. Whereas ~20 % of all cancers are thought to emerge as a result of chronic inflammation [9], more than 80 % of HCCs devel- op in patients with liver cirrhosis [10]. Electronic supplementary material The online version of this article (doi:10.1007/s13402-016-0294-4) contains supplementary material, which is available to authorized users. * Kumaresan Ganesan kumar@oncocellomics.org 1 Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai 625 021, India Cell Oncol. DOI 10.1007/s13402-016-0294-4