Concomitant activation of ETS-like transcription factor-1 and Death Receptor-5 via extracellular signal-regulated kinase in withaferin A-mediated inhibition of hepatocarcinogenesis in mice
PublisherNature Publishing Group
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AbstractHepatocellular carcinoma (HCC) has the second lowest 5-year survival rate (~16%) of all tumor types partly owing to the lack of effective therapeutic agents. Withaferin A (WA) is a bioactive molecule derived from Withania somnifera and the present study is designed to systemically investigate the anti-HCC efficacy of WA. WA inhibited growth, migration and invasion of HCC cells. Using a phospho-kinase screening array, we discovered that WA increased phosphorylation of ERK and p38 in HCC. Further analyses revealed a key role of ERK leading to increased phosphorylation of p90-ribosomal S6 kinase (RSK) and a concomitant activation of ETS-like transcription factor-1(ELK1) and Death Receptor protein-5 (DR5) in HCC. Importantly, oral administration of WA effectively inhibited HepG2-xenografts and DEN-induced-HCC in C57BL/6 mice. Analyses of WA-treated HepG2-xenografts and DEN-induced-HCC tumors showed elevated levels of ERK, RSK, ELK1 and DR5 along with decreased expression of Ki67. In silico analyses of HCC, utilizing published profiling studies showed an inverse correlation between DR5 and Ki67. These data showed the efficacy of WA as an effective agent for HCC inhibition and provided first in vitro and in vivo evidence supporting the key role of a novel crosstalk between WA, ERK/RSK, ELK1, and DR5 in HCC inhibition. Copyright 2017 The Author(s).
SponsorsThis work was supported by NIH R21CA185943 (NKS); NIH R01CA131294, NIH R21CA155686, NIH R01CA204555, Avon Foundation, Breast Cancer Research Foundation 90047965 and The Fetting Fund (DS).
Antineoplastic Agents--therapeutic use
MAP Kinase Signaling System
Receptors, TNF-Related Apoptosis-Inducing Ligand--metabolism
ets-Domain Protein Elk-1metabolism
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85038864361&doi=10.1038%2fs41598-017-18190-4&partnerID=40&md5=317c860b72d216a86c4399c5eab3fe70; http://hdl.handle.net/10713/11299