Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cells.
Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cells.
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DOI：
10.1186/1471-2407-14-179
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发表时间：
2014-03-13
期刊：
影响因子：
3.8
通讯作者：
Fujii T
中科院分区：
文献类型：
--
作者：
Miyasaka A;Oda K;Ikeda Y;Wada-Hiraike O;Kashiyama T;Enomoto A;Hosoya N;Koso T;Fukuda T;Inaba K;Sone K;Uehara Y;Kurikawa R;Nagasaka K;Matsumoto Y;Arimoto T;Nakagawa S;Kuramoto H;Miyagawa K;Yano T;Kawana K;Osuga Y;Fujii T
PTEN失活是子宫内膜癌中最常见的遗传畸变。PTEN的磷酸酶非依赖性作用之一与细胞核中的同源重组（HR）相关。聚（ADP-核糖）聚合酶（PARP）在DNA单链断裂的修复中起关键作用，PARP抑制剂在HR缺陷的癌细胞中诱导合成致死性。我们研究了PARP抑制剂奥拉帕尼的抗肿瘤活性及其在子宫内膜癌细胞系中的敏感性和PTEN状态之间的相关性。在16种子宫内膜癌细胞系中，使用克隆形成试验和SF 50值（抑制细胞存活至50%的浓度）评价了对奥拉帕尼的反应。通过克隆形成试验、RAD 51和γ H2 AX的病灶形成以及裂解PARP的诱导，在亲本HEC-6（PTEN-null）和HEC-6 PTEN +（稳定表达野生型PTEN）细胞之间比较了PTEN对奥拉帕尼和电离辐射（IR）暴露敏感性的影响。在具有野生型PTEN的细胞中分析siRNA对PTEN的作用。在4个（25%：敏感）细胞系中，SF 50值为100 nM或更低;而在4个（25%：耐药）细胞系中，SF 50值为1，000 nM或更高。PTEN突变与奥拉帕尼敏感性无关（突变体[n = 12]：746 ± 838 nM;野生型[n = 4]：215 ± 85 nM，p = 0.26，通过Student t检验）。在16个细胞系中广泛观察到RAD 51表达，并且与PTEN状态无关。在HEC-6PTEN+细胞中，PTEN的引入不影响克隆形成试验中的集落数、RAD 51和γ H2 AX的灶形成以及对凋亡的诱导。在HEC-6-PTEN +细胞中，在IR后24 h内，核PTEN的表达水平没有升高。此外，通过siRNA敲低PTEN并没有改变2个具有野生型PTEN的细胞系对奥拉帕尼的敏感性。我们的研究结果表明，奥拉帕尼，PARP抑制剂，对某些子宫内膜癌细胞系有效。PTEN的失活可能不影响DNA修复功能。预测性生物标志物有必要在子宫内膜癌中使用奥拉帕尼。
PTEN inactivation is the most frequent genetic aberration in endometrial cancer. One of the phosphatase-independent roles of PTEN is associated with homologous recombination (HR) in nucleus. Poly (ADP-ribose) polymerase (PARP) plays key roles in the repair of DNA single-strand breaks, and a PARP inhibitor induces synthetic lethality in cancer cells with HR deficiency. We examined the anti-tumor activity of olaparib, a PARP inhibitor, and its correlation between the sensitivity and status of PTEN in endometrial cancer cell lines. The response to olaparib was evaluated using a clonogenic assay with SF50 values (concentration to inhibit cell survival to 50%) in 16 endometrial cancer cell lines. The effects of PTEN on the sensitivity to olaparib and ionizing radiation (IR) exposure were compared between parental HEC-6 (PTEN-null) and HEC-6 PTEN + (stably expressing wild-type PTEN) cells by clonogenic assay, foci formation of RAD51 and γH2AX, and induction of cleaved PARP. The effects of siRNA to PTEN were analyzed in cells with wild-type PTEN. The SF50 values were 100 nM or less in four (25%: sensitive) cell lines; whereas, SF50 values were 1,000 nM or more in four (25%: resistant) cell lines. PTEN mutations were not associated with sensitivity to olaparib (Mutant [n = 12]: 746 ± 838 nM; Wild-type [n = 4]: 215 ± 85 nM, p = 0.26 by Student’s t test). RAD51 expression was observed broadly and was not associated with PTEN status in the 16 cell lines. The number of colonies in the clonogenic assay, the foci formation of RAD51 and γH2AX, and the induction of apoptosis were not affected by PTEN introduction in the HEC-6 PTEN + cells. The expression level of nuclear PTEN was not elevated within 24 h following IR in the HEC-6-PTEN + cells. In addition, knocking down PTEN by siRNA did not alter the sensitivity to olaparib in 2 cell lines with wild-type PTEN. Our results suggest that olaparib, a PARP inhibitor, is effective on certain endometrial cancer cell lines. Inactivation of PTEN might not affect the DNA repair function. Predictive biomarkers are warranted to utilize olaparib in endometrial cancer.
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影响因子：
3.7
作者：
Chatterjee P;Choudhary GS;Sharma A;Singh K;Heston WD;Ciezki J;Klein EA;Almasan A
通讯作者：
Almasan A
影响因子：
11.2
作者：
McCabe, Nuala;Turner, Nicholas C.;Ashworth, Alan
通讯作者：
Ashworth, Alan
影响因子：
4.3
作者：
Dedes, Konstantin J.;Wilkerson, Paul M.;Reis-Filho, Jorge S.
通讯作者：
Reis-Filho, Jorge S.
影响因子：
7.3
作者：
Menear, Keith A.;Adcock, Claire;Martin, Niall M. B.
通讯作者：
Martin, Niall M. B.
影响因子：
64.5
作者：
Shen, Wen Hong;Balajee, Adayabalam S.;Yin, Yuxin
通讯作者：
Yin, Yuxin