title: Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation.
abstract: Withanolide E, a steroidal lactone from Physalis peruviana, was found to be highly active for sensitizing renal carcinoma cells and a number of other human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Withanolide E, the most potent and least toxic of five TRAIL-sensitizing withanolides identified, enhanced death receptor-mediated apoptotic signaling by a rapid decline in the levels of cFLIP proteins. Other mechanisms by which TRAIL sensitizers have been reported to work: generation of reactive oxygen species (ROS), changes in pro-and antiapoptotic protein expression, death receptor upregulation, activation of intrinsic (mitochondrial) apoptotic pathways, ER stress, and proteasomal inhibition proved to be irrelevant to withanolide E activity. Loss of cFLIP proteins was not due to changes in expression, but rather destabilization and/or aggregation, suggesting impairment of chaperone proteins leading to degradation. Indeed, withanolide E treatment altered the stability of a number of HSP90 client proteins, but with greater apparent specificity than the well-known HSP90 inhibitor geldanamycin. As cFLIP has been reported to be an HSP90 client, this provides a potentially novel mechanism for sensitizing cells to TRAIL. Sensitization of human renal carcinoma cells to TRAIL-induced apoptosis by withanolide E and its lack of toxicity were confirmed in animal studies. Owing to its novel activity, withanolide E is a promising reagent for the analysis of mechanisms of TRAIL resistance, for understanding HSP90 function, and for further therapeutic development. In marked contrast to bortezomib, among the best currently available TRAIL sensitizers, withanolide E's more specific mechanism of action suggests minimal toxic side effects.
authors.affiliation: 1] Molecular Targets Laboratory, NCI-Frederick, Frederick, MD, USA [2] Basic Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Henrich
authors.affiliation: 1] Basic Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA [2] Laboratory for Experimental Immunology and Cancer Inflammation Program, NCI-Frederick, Frederick, MD, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Brooks
authors.affiliation: 1] Molecular Targets Laboratory, NCI-Frederick, Frederick, MD, USA [2] Department of Chemistry, Clark University, Worcester, MA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Erickson
authors.affiliation: Molecular Targets Laboratory, NCI-Frederick, Frederick, MD, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Thomas
authors.affiliation: 1] Molecular Targets Laboratory, NCI-Frederick, Frederick, MD, USA [2] Basic Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: H R
authors.initials: HR
authors.lastname: Bokesch
authors.affiliation: 1] Basic Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA [2] Laboratory for Experimental Immunology and Cancer Inflammation Program, NCI-Frederick, Frederick, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Tewary
authors.affiliation: Laboratory for Experimental Immunology and Cancer Inflammation Program, NCI-Frederick, Frederick, MD, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Thompson
authors.affiliation: Laboratory for Experimental Immunology and Cancer Inflammation Program, NCI-Frederick, Frederick, MD, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Pompei
authors.affiliation: Molecular Targets Laboratory, NCI-Frederick, Frederick, MD, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Gustafson
authors.affiliation: Molecular Targets Laboratory, NCI-Frederick, Frederick, MD, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: McMahon
authors.affiliation: 1] Basic Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA [2] Laboratory for Experimental Immunology and Cancer Inflammation Program, NCI-Frederick, Frederick, MD, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Sayers
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D008807:Mice, Inbred BALB C; D017382:Reactive Oxygen Species / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D054358:Withanolides / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; D054358:Withanolides