title: Mechanistic elucidation of the antitumor properties of withaferin a in breast cancer.
abstract: Withaferin A (WFA) is a steroidal lactone with antitumor effects manifested at multiple levels that are mechanistically obscure. Using a phospho-kinase screening array, we discovered that WFA activated phosphorylation of the S6 kinase RSK (ribosomal S6 kinase) in breast cancer cells. Pursuing this observation, we defined activation of extracellular signal-regulated kinase (ERK)-RSK and ETS-like transcription factor 1 (Elk1)-CHOP (C-EBP homologous protein) kinase pathways in upregulating transcription of the death receptor 5 (DR5). Through this route, WFA acted as an effective DR5 activator capable of potentiating the biologic effects of celecoxib, etoposide, and TRAIL. Accordingly, WFA treatment inhibited breast tumor formation in xenograft and mouse mammary tumor virus (MMTV)-neu mouse models in a manner associated with activation of the ERK/RSK axis, DR5 upregulation, and elevated nuclear accumulation of Elk1 and CHOP. Together, our results offer mechanistic insight into how WFA inhibits breast tumor growth.
authors.affiliation: Authors' Affiliations: Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Department of Medicine, University of Maryland School of Medicine, Baltimore Maryland; and Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Nagalingam
authors.forename: Panjamurthy
authors.initials: P
authors.lastname: Kuppusamy
authors.forename: Shivendra V
authors.initials: SV
authors.lastname: Singh
authors.forename: Dipali
authors.initials: D
authors.lastname: Sharma
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Saxena
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D054358:Withanolides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; C497249:DDIT3 protein, human; C494112:ELK1 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D054358:Withanolides; D050807:ets-Domain Protein Elk-1; D051742:Transcription Factor CHOP; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C009684:withaferin A
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