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Statements

Subject Item
n2:RIV%2F61989592%3A15110%2F14%3A33145176%21RIV15-MSM-15110___
rdf:type
n8:Vysledek skos:Concept
dcterms:description
Glioblastoma-initiating cells (GICs) are self-renewing tumorigenic sub-populations, contributing to therapeutic resistance via decreased sensitivity to ionizing radiation (IR). GIC survival following IR is attributed to an augmented response to genotoxic stress. We now report that GICs are primed to handle additional stress due to basal activation of single-strand break repair (SSBR), the main DNA damage response pathway activated by reactive oxygen species (ROS), compared with non-GICs. ROS levels were higher in GICs and likely contributed to the oxidative base damage and single-strand DNA breaks found elevated in GICs. To tolerate constitutive DNA damage, GICs exhibited a reliance on the key SSBR mediator, poly-ADP-ribose polymerase (PARP), with decreased viability seen upon small molecule inhibition to PARP. PARP inhibition (PARPi) sensitized GICs to radiation and inhibited growth, self-renewal, and DNA damage repair. In vivo treatment with PARPi and radiotherapy attenuated radiation-induced enrichment of GICs and inhibited the central cancer stem cell phenotype of tumor initiation. These results indicate that elevated PARP activation within GICs permits exploitation of this dependence, potently augmenting therapeutic efficacy of IR against GICs. In addition, our results support further development of clinical trials with PARPi and radiation in glioblastoma. Glioblastoma-initiating cells (GICs) are self-renewing tumorigenic sub-populations, contributing to therapeutic resistance via decreased sensitivity to ionizing radiation (IR). GIC survival following IR is attributed to an augmented response to genotoxic stress. We now report that GICs are primed to handle additional stress due to basal activation of single-strand break repair (SSBR), the main DNA damage response pathway activated by reactive oxygen species (ROS), compared with non-GICs. ROS levels were higher in GICs and likely contributed to the oxidative base damage and single-strand DNA breaks found elevated in GICs. To tolerate constitutive DNA damage, GICs exhibited a reliance on the key SSBR mediator, poly-ADP-ribose polymerase (PARP), with decreased viability seen upon small molecule inhibition to PARP. PARP inhibition (PARPi) sensitized GICs to radiation and inhibited growth, self-renewal, and DNA damage repair. In vivo treatment with PARPi and radiotherapy attenuated radiation-induced enrichment of GICs and inhibited the central cancer stem cell phenotype of tumor initiation. These results indicate that elevated PARP activation within GICs permits exploitation of this dependence, potently augmenting therapeutic efficacy of IR against GICs. In addition, our results support further development of clinical trials with PARPi and radiation in glioblastoma.
dcterms:title
Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells
skos:prefLabel
Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells
skos:notation
RIV/61989592:15110/14:33145176!RIV15-MSM-15110___
n3:aktivita
n7:P
n3:aktivity
P(ED0030/01/01), P(EE2.3.09.0027)
n3:cisloPeriodika
2
n3:dodaniDat
n15:2015
n3:domaciTvurceVysledku
n11:6201822 n11:2998556
n3:druhVysledku
n9:J
n3:duvernostUdaju
n14:S
n3:entitaPredkladatele
n5:predkladatel
n3:idSjednocenehoVysledku
50281
n3:idVysledku
RIV/61989592:15110/14:33145176
n3:jazykVysledku
n18:eng
n3:klicovaSlova
PARP; radioresistance; glioma; DNA repair; cancer stem cell
n3:klicoveSlovo
n4:PARP n4:glioma n4:cancer%20stem%20cell n4:DNA%20repair n4:radioresistance
n3:kodStatuVydavatele
GB - Spojené království Velké Británie a Severního Irska
n3:kontrolniKodProRIV
[5D760B0DF9F5]
n3:nazevZdroje
Cell Death & Differentiation
n3:obor
n17:FD
n3:pocetDomacichTvurcuVysledku
2
n3:pocetTvurcuVysledku
11
n3:projekt
n16:ED0030%2F01%2F01 n16:EE2.3.09.0027
n3:rokUplatneniVysledku
n15:2014
n3:svazekPeriodika
21
n3:tvurceVysledku
Bártek, Jiří Flavahan, Wa Rich, Jn Venere, M. Song, La Vasanji, A. Rasmussen, Rd Hamerlík, Petra Wu, Q. Tenley, N. Hjelmeland, Ab
n3:wos
000329787800011
s:issn
1350-9047
s:numberOfPages
12
n19:doi
10.1038/cdd.2013.136
n13:organizacniJednotka
15110