Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.11241
Title: PRIMA-1 targets the vulnerability of multiple myeloma of deregulated protein homeostasis through the perturbation of ER stress via p73 demethylation
Authors: Teoh P.J. 
Bi C.
Sintosebastian C.
Tay L.S. 
Fonseca R.
Chng W.J. 
Keywords: antineoplastic agent
bortezomib
growth arrest and DNA damage inducible protein 153
heat shock protein 70
initiation factor 2alpha
membrane protein
messenger RNA
nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase
p53 reactivation and induction of massive apoptosis 1
protein GADD34
protein p53
protein p73
unclassified drug
activating transcription factor 6
ATF6 protein, human
bortezomib
DNA (cytosine 5) methyltransferase 1
DNMT1 protein, human
ERN1 protein, human
membrane protein
nerve protein
p73 protein, human
PRIMA1 protein, human
protein serine threonine kinase
ribonuclease
tumor protein p73
antineoplastic activity
apoptosis
Article
bioinformatics
cancer inhibition
cell survival
cell viability
concentration response
controlled study
demethylation
drug cytotoxicity
drug mechanism
drug potency
drug sensitization
drug targeting
endoplasmic reticulum stress
gene
genotype
human
human cell
IC50
intracellular signaling
molecular dynamics
multiple myeloma
myeloma cell
protein conformation
protein expression
protein homeostasis
protein phosphorylation
TP73 gene
transcription regulation
unfolded protein response
upregulation
DNA methylation
endoplasmic reticulum
gene expression regulation
gene silencing
genetic transcription
genome-wide association study
homeostasis
metabolism
multiple myeloma
tumor cell line
Activating Transcription Factor 6
Apoptosis
Bortezomib
Cell Line, Tumor
Cell Survival
DNA (Cytosine-5-)-Methyltransferase 1
DNA Methylation
Endoplasmic Reticulum
Endoribonucleases
Gene Expression Regulation, Neoplastic
Gene Silencing
Genome-Wide Association Study
Genotype
Homeostasis
Humans
Membrane Proteins
Multiple Myeloma
Nerve Tissue Proteins
Protein-Serine-Threonine Kinases
Transcription, Genetic
Tumor Protein p73
Unfolded Protein Response
Up-Regulation
Issue Date: 2016
Publisher: Impact Journals LLC
Citation: Teoh P.J., Bi C., Sintosebastian C., Tay L.S., Fonseca R., Chng W.J. (2016). PRIMA-1 targets the vulnerability of multiple myeloma of deregulated protein homeostasis through the perturbation of ER stress via p73 demethylation. Oncotarget 7 (38) : 61806-61819. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.11241
Abstract: Despite therapeutic advancement, multiple myeloma (MM) remains incurable with drug resistance being one of the main challenges in the clinic. Myeloma cells possess high protein secretory load, leading to increased intracellular endoplasmic reticulum (ER) stress. Hence, they are vulnerable to further perturbation to its protein homeostasis. In studying the therapeutic mechanism of PRIMA-1 (mutant-p53- reactivating-agent), we uncovered its novel p53-independent-mechanism that can be exploited for myeloma. Despite its inability in restoring the wild type-p53 protein conformation and transcriptional function in the mutant-p53-human-myeloma-cells, PRIMA-1 was efficacious against myeloma cells with differential p53 genotypes. Strikingly, cells without p53 expression demonstrated highest drug sensitivity. Genome-wide gene-expression analysis revealed the involvement of ER stress/UPRpathway in inducing PRIMA-1-toxicity. UPR markers, HSP70, CHOP and GADD34, were significantly up-regulated, concomitantly with the induction of apoptosis. Furthermore, there was a global attenuation of protein synthesis, correlated with phospho-eIF2a up-regulation. Mechanistically, we identified that PRIMA-1 could cause the demethylation of TP73, through DNMT1 depletion, to subsequently enhance UPR. Of clinical significance, we observed that PRIMA-1 had additive therapeutic effects with another UPR-inducing-agent, bortezomib. Importantly, it can partially re-sensitize bortezomib-resistant cells to bortezomib. Given that MM is already stressed at the baseline in the ER, our results implicated that PRIMA-1 is a potential therapeutic option in MM by targeting its Achilles heel.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/175452
ISSN: 19492553
DOI: 10.18632/oncotarget.11241
Appears in Collections:Staff Publications
Elements

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
10_18632_oncotarget_11241.pdf5.48 MBAdobe PDF

OPEN

NoneView/Download

Google ScholarTM

Check

Altmetric


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