PARP inhibition sensitizes to low dose-rate radiation TMPRSS2-ERG fusion gene-expressing and PTEN-deficient prostate cancer cells.
PARP inhibition sensitizes to low dose-rate radiation TMPRSS2-ERG fusion gene-expressing and PTEN-deficient prostate cancer cells.
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DOI：
10.1371/journal.pone.0060408
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Almasan A
中科院分区：
文献类型：
--
作者：
Chatterjee P;Choudhary GS;Sharma A;Singh K;Heston WD;Ciezki J;Klein EA;Almasan A
暴露于遗传毒性剂，如辐射，会产生DNA损伤，当DNA修复受损时，其毒性会增强。聚（ADP-核糖）聚合酶（PARP）抑制剂被发现在BRCA 1和BRCA 2缺陷的细胞中是“合成致死”的，这会损害同源重组。然而，由于许多肿瘤，包括前列腺癌（PCa）很少有这样的突变，有相当大的兴趣在寻找替代决定因素的PARP抑制剂的敏感性。我们评估了放射与PARP抑制剂rucaparib联合应用在PCa细胞中的有效性。放射和rucaparib处理后的克隆形成存活的组合指数显示了一组PCa细胞系中的协同相互作用，对于表达ETS基因融合蛋白的LNCaP和VCaP细胞最强。这些发现与衰老激活的协同相互作用相关，如β-半乳糖苷酶染色所示。因此，PTEN的缺失和ETS基因融合的存在促进了衰老的激活，这有助于降低克隆存活率。rucaparib存在下放射敏感性增加与持续性DNA断裂相关，如通过χ-H2 AX、p53 BP 1和Rad 51灶所确定。携带TMPRSS 2-ERG基因融合体的VCaP细胞和稳定表达类似构建体（融合体III）的PC 3细胞显示出对rucaparib的敏感性增强，这反过来又将辐射反应增加到与DNA-PKcs抑制剂NU 7441相似的程度。Rucaparib放射致敏PCa细胞，在较长时间内给予低剂量率辐射（LDR）具有明显的益处，导致DNA损伤增强。在临床上成功使用的LDR模拟近距离放射治疗在与rucaparib联合使用时最有效，诱导持续的DNA损伤和衰老，导致克隆形成存活率降低。该组合在存在TMPRSS 2-ERG和不存在PTEN的情况下是最有效的，表明在患有中度和高度风险PCa的患者中进行近距离放射治疗的临床潜力。
Exposure to genotoxic agents, such as irradiation produces DNA damage, the toxicity of which is augmented when the DNA repair is impaired. Poly (ADP-ribose) polymerase (PARP) inhibitors were found to be “synthetic lethal” in cells deficient in BRCA1 and BRCA2 that impair homologous recombination. However, since many tumors, including prostate cancer (PCa) rarely have on such mutations, there is considerable interest in finding alternative determinants of PARP inhibitor sensitivity. We evaluated the effectiveness of radiation in combination with the PARP inhibitor, rucaparib in PCa cells. The combination index for clonogenic survival following radiation and rucaparib treatments revealed synergistic interactions in a panel of PCa cell lines, being strongest for LNCaP and VCaP cells that express ETS gene fusion proteins. These findings correlated with synergistic interactions for senescence activation, as indicated by β--galactosidase staining. Absence of PTEN and presence of ETS gene fusion thus facilitated activation of senescence, which contributed to decreased clonogenic survival. Increased radiosensitivity in the presence of rucaparib was associated with persistent DNA breaks, as determined by χ-H2AX, p53BP1, and Rad51 foci. VCaP cells, which harbor the TMPRSS2-ERG gene fusion and PC3 cells that stably express a similar construct (fusion III) showed enhanced sensitivity towards rucaparib, which, in turn, increased the radiation response to a similar extent as the DNA-PKcs inhibitor NU7441. Rucaparib radiosensitized PCa cells, with a clear benefit of low dose-rate radiation (LDR) administered over a longer period of time that caused enhanced DNA damage. LDR mimicking brachytherapy, which is used successfully in the clinic, was most effective when combined with rucaparib by inducing persistent DNA damage and senescence, leading to decreased clonogenic survival. This combination was most effective in the presence of the TMPRSS2-ERG and in the absence of PTEN, indicating clinical potential for brachytherapy in patients with intermediate and high risk PCa.
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影响因子：
30.8
作者：
Carver, Brett S.;Tran, Jennifer;Gopalan, Anuradha;Chen, Zhenbang;Shaikh, Safa;Carracedo, Arkaitz;Alimonti, Andrea;Nardella, Caterina;Varmeh, Shohreh;Scardino, Peter T.;Cordon-Cardo, Carlos;Gerald, William;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo
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5.7
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Williams KJ
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5.7
作者：
Liu, Stanley K.;Coackley, Carla;Bristow, Robert G.
通讯作者：
Bristow, Robert G.
影响因子：
5.3
作者：
Mazumder, Suparna;Plesca, Dragos;Almasan, Alexandru
通讯作者：
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影响因子：
4.3
作者：
Oplustilova, Lenka;Wolanin, Kamila;Bartek, Jiri
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