Evidence map›Paper›PMID 25719250›Full record

ArticleCell death & disease2015

Withanolide E sensitizes renal carcinoma cells to TRAIL-induced apoptosis by increasing cFLIP degradation.

C J Henrich, A D Brooks, K L Erickson, C L Thomas, H R Bokesch, P Tewary, C R Thompson, R J Pompei, K R Gustafson, J B McMahon and 1 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell death & disease, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.

0numbers the graph read from it
0cells of the map it votes in
33citing papers in PubMed
20.0field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

33 citing papers in PubMed, 58 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 3 institutions in 1 country.

C J Henrich1] 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.
A D Brooks1] 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.
K L Erickson1] Molecular Targets Laboratory, NCI-Frederick, Frederick, MD, USA [2] Department of Chemistry, Clark University, Worcester, MA, USA.
C L ThomasMolecular Targets Laboratory, NCI-Frederick, Frederick, MD, USA.
H R Bokesch1] 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.
P Tewary1] 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.
C R ThompsonLaboratory for Experimental Immunology and Cancer Inflammation Program, NCI-Frederick, Frederick, MD, USA.
R J PompeiLaboratory for Experimental Immunology and Cancer Inflammation Program, NCI-Frederick, Frederick, MD, USA.
K R GustafsonMolecular Targets Laboratory, NCI-Frederick, Frederick, MD, USA.
J B McMahonMolecular Targets Laboratory, NCI-Frederick, Frederick, MD, USA.
T J Sayers1] 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.
Target (United States) · USFrederick National Laboratory for Cancer Research · USLeidos (United States) · US

Funding

Natural Products Discovery and Characterization Through Network CollaborationsZIABC011568 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI DU, LIN · 2014 to 2025
$17.2M
CCR NIH HHS HHSN261200800001CIntramural NIH HHSNCI NIH HHS HHSN261200800001E
6 · The paper itself

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.

Indexed as

AnimalsApoptosisBlotting, WesternCarcinoma, Renal CellCell Line, TumorEndoplasmic Reticulum StressHumansImmunoprecipitationMice, Inbred BALB CReactive Oxygen SpeciesTNF-Related Apoptosis-Inducing LigandWithanolidesReactive Oxygen SpeciesTNF-Related Apoptosis-Inducing LigandWithanolides

Identifiers

PMID25719250
PMCPMC4669816
OpenAlexW1965564922

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.