Please use this identifier to cite or link to this item: https://doi.org/10.1038/cddis.2013.413
Title: Small molecule sensitization to TRAIL is mediated via nuclear localization, phosphorylation and inhibition of chaperone activity of Hsp27
Authors: Mellier, G.
Liu, D.
Bellot, G. 
Lisa Holme, A.
Pervaiz, S.
Keywords: Apoptosis
Drug resistance
Hsp27
LY303511
TRAIL
Issue Date: Oct-2013
Citation: Mellier, G., Liu, D., Bellot, G., Lisa Holme, A., Pervaiz, S. (2013-10). Small molecule sensitization to TRAIL is mediated via nuclear localization, phosphorylation and inhibition of chaperone activity of Hsp27. Cell Death and Disease 4 (10) : -. ScholarBank@NUS Repository. https://doi.org/10.1038/cddis.2013.413
Abstract: The small chaperone protein Hsp27 confers resistance to apoptosis, and therefore is an attractive anticancer drug target. We report here a novel mechanism underlying the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitizing activity of the small molecule LY303511, an inactive analog of the phosphoinositide 3-kinase inhibitor inhibitor LY294002, in HeLa cells that are refractory to TRAIL-induced apoptosis. On the basis of the fact that LY303511 is derived from LY294002, itself derived from quercetin, and earlier findings indicating that quercetin and LY294002 affected Hsp27 expression, we investigated whether LY303511 sensitized cancer cells to TRAIL via a conserved inhibitory effect on Hsp27. We provide evidence that upon treatment with LY303511, Hsp27 is progressively sequestered in the nucleus, thus reducing its protective effect in the cytosol during the apoptotic process. LY303511-induced nuclear translocation of Hsp27 is linked to its sustained phosphorylation via activation of p38 kinase and MAPKAP kinase 2 and the inhibition of PP2A. Furthermore, Hsp27 phosphorylation leads to the subsequent dissociation of its large oligomers and a decrease in its chaperone activity, thereby further compromising the death inhibitory activity of Hsp27. Furthermore, genetic manipulation of Hsp27 expression significantly affected the TRAIL sensitizing activity of LY303511, which corroborated the Hsp27 targeting activity of LY303511. Taken together, these data indicate a novel mechanism of small molecule sensitization to TRAIL through targeting of Hsp27 functions, rather than its overall expression, leading to decreased cellular protection, which could have therapeutic implications for overcoming chemotherapy resistance in tumor cells. © 2013 Macmillan Publishers Limited. All rights reserved.
Source Title: Cell Death and Disease
URI: http://scholarbank.nus.edu.sg/handle/10635/108548
ISSN: 20414889
DOI: 10.1038/cddis.2013.413
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
2013-Small_molecule_sensitization_TRAIL_mediated-published.pdf1.75 MBAdobe PDF

OPEN

PublishedView/Download

SCOPUSTM   
Citations

7
checked on Dec 10, 2018

WEB OF SCIENCETM
Citations

7
checked on Dec 10, 2018

Page view(s)

44
checked on Nov 23, 2018

Download(s)

7
checked on Nov 23, 2018

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.