Evidence map›Paper›PMID 26913603›Full record

ArticleCell death & disease2016

Inhibition of AKT promotes FOXO3a-dependent apoptosis in prostate cancer.

T P Das, S Suman, H Alatassi, M K Ankem, C Damodaran

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

Article in Cell death & disease, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
85citing papers in PubMed, 1 pooled it
8.2field-weighted citation impact, top 2% 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

85 citing papers in PubMed, 1 synthesis or guideline pooled it, 129 citations in OpenAlex.

  1. Pooled it
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  5. Review
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25 more citing papers are in PubMed but not listed here.

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

5 authors at 1 institution in 1 country.

T P DasDepartment of Urology, University of Louisville, Louisville, KY 40202, USA.
S SumanDepartment of Urology, University of Louisville, Louisville, KY 40202, USA.
H AlatassiDepartment of Pathology, University of Louisville, Louisville, KY 40202, USA.
M K AnkemDepartment of Urology, University of Louisville, Louisville, KY 40202, USA.
C DamodaranDepartment of Urology, University of Louisville, Louisville, KY 40202, USA.
University of Louisville · US

Funding

Targeting AR and Akt for the Treatment of Prostate CancerR01CA138797 · NCI · UNIVERSITY OF LOUISVILLE · PI DAMODARAN, CHENDIL · 2010 to 2015
$1.5M
Dietary prevention of prostate cancerR01CA140605 · NCI · UNIVERSITY OF LOUISVILLE · PI DAMODARAN, CHENDIL · 2010 to 2015
$1.5M
NCI NIH HHS R01 CA138797NCI NIH HHS R01CA138797NCI NIH HHS R01 CA140605NCI NIH HHS R01CA140605
6 · The paper itself

Abstract

Growth factor-induced activation of protein kinase-B (PKB), also known as AKT, induces pro-survival signaling and inhibits activation of pro-apoptotic signaling molecules including the Forkhead box O-3a (FOXO3a) transcription factor and caspase in transformed prostate cells in vitro. Earlier we reported that Withaferin-A (WA), a small herbal molecule, induces pro-apoptotic response-4 (Par-4) mediated apoptosis in castration-resistant prostate cancer (CRPC) cells. In the present study, we demonstrate that inhibition of AKT facilitates nuclear shuttling of FOXO3a where it regulates Par-4 transcription in CRPC cells. FOXO3a is upstream of Par-4 signaling, which is required for induction of apoptosis in CRPC cells. Promoter bashing studies and Ch-IP analysis confirm a direct interaction of FOXO3a and Par-4; a sequential deletion of FOXO3a-binding sites in the Par-4 promoter fails to induce Par-4 activation. To confirm these observations, we either overexpressed AKT or silenced FOXO3a activation in CRPC cells. Both methods inhibit Par-4 function and apoptosis is significantly compromised. In xenograft tumors derived from AKT-overexpressed CRPC cells, FOXO3a and Par-4 expression is downregulated, leading to aggressive tumor growth. Oral administration of WA to mice with xenograft tumors restores FOXO3a-mediated Par-4 functions and results in inhibited tumor growth. Finally, an inverse correlation of nuclear localization of AKT expression corresponds to cytoplasmic Par-4 localization in human prostate tissue array. Our studies suggest that Par-4 is one of the key transcriptional targets of FOXO3a, and Par-4 activation is required for induction of apoptosis in CRPC cells. Activation of FOXO3a appears to be an attractive target for the treatment of CRPC and molecules such as WA can be explored further for the treatment of CRPC.

Indexed as

ApoptosisAnimalsAntineoplastic AgentsApoptosis Regulatory ProteinsBinding SitesCell Line, TumorCell SurvivalForkhead Box Protein O3HumansMaleMiceMice, Inbred BALB CMice, NudePromoter Regions, GeneticProstatic NeoplasmsProto-Oncogene Proteins c-aktAntineoplastic AgentsApoptosis Regulatory ProteinsForkhead Box Protein O3FOXO3 protein, humanprostate apoptosis response-4 proteinProto-Oncogene Proteins c-aktReceptors, Androgenwithaferin AWithanolides

Identifiers

PMID26913603
PMCPMC4849149
OpenAlexW2286659777

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.