PDF(Pubmed)
Abstract：
BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPis) can effectively treat ovarian cancer patients with defective homologous recombination (HR). Loss or dysfunction of PTEN, a typical tumour suppressor, impairs double-strand break (DSB) repair. Hence, we explored the possibility of inhibiting PTEN to induce HR deficiency (HRD) for PARPi application.
METHODS: Functional studies using PTEN inhibitor VO-OHpic and PARPi olaparib were performed to explore the molecular mechanisms in vitro and in vivo.
RESULTS: In this study, the combination of VO-OHpic with olaparib exhibited synergistic inhibitory effects on ovarian cancer cells was demonstrated. Furthermore, VO-OHpic was shown to enhance DSBs by reducing nuclear expression of PTEN and inhibiting HR repair through the modulation of MRE11-RAD50-NBN (MRN) complex, critical for DSB repair. TCGA and GTEx analysis revealed a strong correlation between PTEN and MRN in ovarian cancer. Mechanistic studies indicated that VO-OHpic reduced expression of MRN, likely by decreasing PTEN/E2F1-mediated transcription. Moreover, PTEN-knockdown inhibited expression of MRN, increased sensitivities to olaparib, and induced DSBs. In vivo experiments showed that the combination of VO-OHpic with olaparib exhibited enhanced inhibitory effects on tumour growth.
CONCLUSIONS: Collectively, this study highlights the potential of PTEN inhibitors in combination therapy with PARPis to create HRD for HRD-negative ovarian cancers.
METHODS: Functional studies using PTEN inhibitor VO-OHpic and PARPi olaparib were performed to explore the molecular mechanisms in vitro and in vivo.
RESULTS: In this study, the combination of VO-OHpic with olaparib exhibited synergistic inhibitory effects on ovarian cancer cells was demonstrated. Furthermore, VO-OHpic was shown to enhance DSBs by reducing nuclear expression of PTEN and inhibiting HR repair through the modulation of MRE11-RAD50-NBN (MRN) complex, critical for DSB repair. TCGA and GTEx analysis revealed a strong correlation between PTEN and MRN in ovarian cancer. Mechanistic studies indicated that VO-OHpic reduced expression of MRN, likely by decreasing PTEN/E2F1-mediated transcription. Moreover, PTEN-knockdown inhibited expression of MRN, increased sensitivities to olaparib, and induced DSBs. In vivo experiments showed that the combination of VO-OHpic with olaparib exhibited enhanced inhibitory effects on tumour growth.
CONCLUSIONS: Collectively, this study highlights the potential of PTEN inhibitors in combination therapy with PARPis to create HRD for HRD-negative ovarian cancers.
摘要：
背景：聚（ADP-核糖）聚合酶抑制剂（PARPis）可以有效治疗同源重组（HR）缺陷的卵巢癌患者。PTEN缺失或功能障碍，典型的肿瘤抑制因子,损害双股断裂（DSB）的修复。因此，我们探讨了抑制PTEN诱导PARPi应用的HR缺乏（HRD）的可能性。
方法：使用PTEN抑制剂VO-OHpic和PARPiolaparib进行功能研究，以探索体外和体内的分子机制。
结果：在这项研究中，证明了VO-OHpic与奥拉帕尼的组合对卵巢癌细胞具有协同抑制作用。此外，显示VO-OHpic通过减少PTEN的核表达并通过调节MRE11-RAD50-NBN（MRN）复合物抑制HR修复来增强DSB，对于DSB修复至关重要。TCGA和GTEx分析显示PTEN和MRN在卵巢癌中具有很强的相关性。机制研究表明VO-OHpic降低MRN的表达，可能是通过降低PTEN/E2F1介导的转录。此外，PTEN敲除抑制MRN表达,对奥拉帕尼的敏感性增加，和诱导的DSB。体内实验表明，VO-OHpic与奥拉帕尼的组合对肿瘤生长具有增强的抑制作用。
结论：总的来说，这项研究强调了PTEN抑制剂与PARPis联合治疗HRD阴性卵巢癌的潜力.
方法：使用PTEN抑制剂VO-OHpic和PARPiolaparib进行功能研究，以探索体外和体内的分子机制。
结果：在这项研究中，证明了VO-OHpic与奥拉帕尼的组合对卵巢癌细胞具有协同抑制作用。此外，显示VO-OHpic通过减少PTEN的核表达并通过调节MRE11-RAD50-NBN（MRN）复合物抑制HR修复来增强DSB，对于DSB修复至关重要。TCGA和GTEx分析显示PTEN和MRN在卵巢癌中具有很强的相关性。机制研究表明VO-OHpic降低MRN的表达，可能是通过降低PTEN/E2F1介导的转录。此外，PTEN敲除抑制MRN表达,对奥拉帕尼的敏感性增加，和诱导的DSB。体内实验表明，VO-OHpic与奥拉帕尼的组合对肿瘤生长具有增强的抑制作用。
结论：总的来说，这项研究强调了PTEN抑制剂与PARPis联合治疗HRD阴性卵巢癌的潜力.
