Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Urology Research Institute, Guangdong Key Laboratory of Urology, Guangzhou 510230, P.R. China.
Oncol Rep. 2018 Apr;39(4):1901-1909. doi: 10.3892/or.2018.6238. Epub 2018 Jan 26.
Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib or rucaparib, have shown treatment efficacy in BRCA1/2-deficient tumors. However, since PARP inhibitors (PARPi) mainly modulate the activation of PARP but not its expression, whether small interfering RNA (siRNA) specific to PARP has the same function as PARPi has not been well defined. In the present study it was demonstrated that PARP1-siRNA could reduce prostate cancer (PCa) cell progression regardless of the BRCA1/2 mutation. PARP1 silencing could significantly inhibit PC3 cell migration and invasion. Additionally, PARP1-siRNA also inhibited the proliferation of PC3 and Du145 cells. After the induction of apoptosis by docetaxel, cleaved-caspase3 of DU145 and C4-2 cells increased significantly in the PARP1-siRNA group. In the xenograft nude mouse model, PARP1-siRNA could suppress xenograft tumor size of PC3 cells and produce a more regular morphology. In vitro and in vivo, PARP1 silencing significantly downregulated vimentin expression and upregulated E-cadherin expression, both of which are epithelial-mesenchymal transition (EMT) markers. It has been revealed that PI3K inhibition could sensitize the effect of PARPi. Notably, PARP1-siRNA could suppress the expression of EGFR and p-GSK3β (Ser9) in PCa cells, which was different from PARPi. Our results indicated that PARP1-siRNA can suppress the growth and invasion capacity of PCa cells, thereby suggesting that PARP1-siRNA, which is different from PARPi, may provide a potential treatment method for PCa.
聚（ADP-核糖）聚合酶（PARP）抑制剂，如奥拉帕利或鲁卡帕利，已显示出在 BRCA1/2 缺陷型肿瘤中的治疗效果。然而，由于 PARP 抑制剂（PARPi）主要调节 PARP 的激活而不是其表达，因此针对 PARP 的小干扰 RNA（siRNA）是否具有与 PARPi 相同的功能尚未得到很好的定义。在本研究中，证明了 PARP1-siRNA 可以减少前列腺癌（PCa）细胞的进展，而与 BRCA1/2 突变无关。PARP1 沉默可以显著抑制 PC3 细胞的迁移和侵袭。此外，PARP1-siRNA 还抑制了 PC3 和 Du145 细胞的增殖。在用多西他赛诱导细胞凋亡后，PARP1-siRNA 组中 DU145 和 C4-2 细胞的裂解 caspase3 明显增加。在异种移植裸鼠模型中，PARP1-siRNA 可以抑制 PC3 细胞的异种移植肿瘤大小，并产生更规则的形态。在体内外，PARP1 沉默显著下调波形蛋白的表达，上调上皮-间充质转化（EMT）标志物 E-钙黏蛋白的表达。已经揭示了 PI3K 抑制可以增强 PARPi 的作用。值得注意的是，PARP1-siRNA 可以抑制 PCa 细胞中 EGFR 和 p-GSK3β（Ser9）的表达，这与 PARPi 不同。我们的结果表明，PARP1-siRNA 可以抑制 PCa 细胞的生长和侵袭能力，因此表明与 PARPi 不同的 PARP1-siRNA 可能为 PCa 提供一种潜在的治疗方法。
