ATR 抑制增加了对 PARP 介导的 DNA 修复的依赖,揭示了一种更好的宫颈癌治疗策略。

IF 4.5 2区 医学 Q1 OBSTETRICS & GYNECOLOGY Gynecologic oncology Pub Date : 2024-10-19 DOI:10.1016/j.ygyno.2024.10.009
{"title":"ATR 抑制增加了对 PARP 介导的 DNA 修复的依赖,揭示了一种更好的宫颈癌治疗策略。","authors":"","doi":"10.1016/j.ygyno.2024.10.009","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><div>Cervical cancer results from persistent infection with high-risk human papillomavirus (HR-HPV) and the expression of E6 and E7 oncoproteins. E6 and E7 compromise the activity of p53 and Rb, the G1-S cell cycle checkpoint, and ATM-mediated DNA damage repair (DDR), which in turn increases reliance on ATR- and PARP-mediated DDR at the G2 cell cycle checkpoint. This study aimed to determine the effects of an ATR inhibitor (ATRi, AZD6738) and a PARP-inhibitor (PARPi, AZD2281) on HR-HPV+ cervical cancer cell lines.</div></div><div><h3>Methods</h3><div>The effects of ATRi and PARPi, alone and in combination, on metabolic viability, cell cycle arrest, apoptosis, and DDR pathways in cervical cancer cell lines were evaluated in vitro, and the in vivo tumor response was evaluated using a xenograft model.</div></div><div><h3>Results</h3><div>Cervical cancer cells were sensitive to ATRi and PARPi monotherapy. The combination therapy was only synergistic in reducing metabolic viability when exposed to ATRi first, followed by PARPi, owing to ATRi-mediated upregulation of PARP expression. Combination of ATRi and PARPi induced G2 cell cycle arrest and apoptosis. PARPi induced DNA damage and γH2AX phosphorylation, which was further increased by ATRi treatment. However, PARPi-induced Rad51 foci formation was reduced by ATRi treatment, suggesting the inhibition of homologous recombination repair. ATRi significantly reduced cervical cancer xenograft tumor growth and was not affected by simultaneous PARPi treatment at the doses studied.</div></div><div><h3>Conclusions</h3><div>Our findings show that ATRi increased reliance on PARP for metabolic viability, the combination of ATRi and PARPi induced synthetic lethality in cervical cancer in vitro, and reduced tumor burden in vivo.</div></div>","PeriodicalId":12853,"journal":{"name":"Gynecologic oncology","volume":null,"pages":null},"PeriodicalIF":4.5000,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"ATR inhibition increases reliance on PARP-mediated DNA repair revealing an improved therapeutic strategy for cervical cancer\",\"authors\":\"\",\"doi\":\"10.1016/j.ygyno.2024.10.009\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><div>Cervical cancer results from persistent infection with high-risk human papillomavirus (HR-HPV) and the expression of E6 and E7 oncoproteins. E6 and E7 compromise the activity of p53 and Rb, the G1-S cell cycle checkpoint, and ATM-mediated DNA damage repair (DDR), which in turn increases reliance on ATR- and PARP-mediated DDR at the G2 cell cycle checkpoint. This study aimed to determine the effects of an ATR inhibitor (ATRi, AZD6738) and a PARP-inhibitor (PARPi, AZD2281) on HR-HPV+ cervical cancer cell lines.</div></div><div><h3>Methods</h3><div>The effects of ATRi and PARPi, alone and in combination, on metabolic viability, cell cycle arrest, apoptosis, and DDR pathways in cervical cancer cell lines were evaluated in vitro, and the in vivo tumor response was evaluated using a xenograft model.</div></div><div><h3>Results</h3><div>Cervical cancer cells were sensitive to ATRi and PARPi monotherapy. The combination therapy was only synergistic in reducing metabolic viability when exposed to ATRi first, followed by PARPi, owing to ATRi-mediated upregulation of PARP expression. Combination of ATRi and PARPi induced G2 cell cycle arrest and apoptosis. PARPi induced DNA damage and γH2AX phosphorylation, which was further increased by ATRi treatment. However, PARPi-induced Rad51 foci formation was reduced by ATRi treatment, suggesting the inhibition of homologous recombination repair. ATRi significantly reduced cervical cancer xenograft tumor growth and was not affected by simultaneous PARPi treatment at the doses studied.</div></div><div><h3>Conclusions</h3><div>Our findings show that ATRi increased reliance on PARP for metabolic viability, the combination of ATRi and PARPi induced synthetic lethality in cervical cancer in vitro, and reduced tumor burden in vivo.</div></div>\",\"PeriodicalId\":12853,\"journal\":{\"name\":\"Gynecologic oncology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2024-10-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Gynecologic oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0090825824011594\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"OBSTETRICS & GYNECOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gynecologic oncology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0090825824011594","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OBSTETRICS & GYNECOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

目的:宫颈癌源于高危人类乳头瘤病毒(HR-HPV)的持续感染以及 E6 和 E7 肿瘤蛋白的表达。E6 和 E7 会损害 p53 和 Rb、G1-S 细胞周期检查点以及 ATM 介导的 DNA 损伤修复(DDR)的活性,进而增加 G2 细胞周期检查点对 ATR 和 PARP 介导的 DDR 的依赖。本研究旨在确定ATR抑制剂(ATRi,AZD6738)和PARP抑制剂(PARPi,AZD2281)对HR-HPV+宫颈癌细胞系的影响:方法:在体外评估 ATRi 和 PARPi 单独或联合使用对宫颈癌细胞株代谢活力、细胞周期停滞、细胞凋亡和 DDR 通路的影响,并使用异种移植模型评估体内肿瘤反应:结果:宫颈癌细胞对 ATRi 和 PARPi 单药治疗敏感。结果表明:宫颈癌细胞对 ATRi 和 PARPi 单药治疗均敏感,但由于 ATRi 介导的 PARP 表达上调,联合治疗在降低代谢活力方面只有先暴露于 ATRi 后暴露于 PARPi 的协同作用。ATRi 和 PARPi 联合使用可诱导 G2 细胞周期停滞和细胞凋亡。PARPi 可诱导 DNA 损伤和 γH2AX 磷酸化,而 ATRi 可进一步提高这种磷酸化。然而,PARPi诱导的Rad51病灶形成在ATRi处理后减少,这表明同源重组修复受到了抑制。ATRi能明显降低宫颈癌异种移植瘤的生长,在研究剂量下,ATRi不受同时PARPi治疗的影响:我们的研究结果表明,ATRi 增加了对 PARP 代谢活力的依赖,ATRi 和 PARPi 的联合应用在体外诱导了宫颈癌的合成致死率,并减少了体内的肿瘤负荷。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
ATR inhibition increases reliance on PARP-mediated DNA repair revealing an improved therapeutic strategy for cervical cancer

Objective

Cervical cancer results from persistent infection with high-risk human papillomavirus (HR-HPV) and the expression of E6 and E7 oncoproteins. E6 and E7 compromise the activity of p53 and Rb, the G1-S cell cycle checkpoint, and ATM-mediated DNA damage repair (DDR), which in turn increases reliance on ATR- and PARP-mediated DDR at the G2 cell cycle checkpoint. This study aimed to determine the effects of an ATR inhibitor (ATRi, AZD6738) and a PARP-inhibitor (PARPi, AZD2281) on HR-HPV+ cervical cancer cell lines.

Methods

The effects of ATRi and PARPi, alone and in combination, on metabolic viability, cell cycle arrest, apoptosis, and DDR pathways in cervical cancer cell lines were evaluated in vitro, and the in vivo tumor response was evaluated using a xenograft model.

Results

Cervical cancer cells were sensitive to ATRi and PARPi monotherapy. The combination therapy was only synergistic in reducing metabolic viability when exposed to ATRi first, followed by PARPi, owing to ATRi-mediated upregulation of PARP expression. Combination of ATRi and PARPi induced G2 cell cycle arrest and apoptosis. PARPi induced DNA damage and γH2AX phosphorylation, which was further increased by ATRi treatment. However, PARPi-induced Rad51 foci formation was reduced by ATRi treatment, suggesting the inhibition of homologous recombination repair. ATRi significantly reduced cervical cancer xenograft tumor growth and was not affected by simultaneous PARPi treatment at the doses studied.

Conclusions

Our findings show that ATRi increased reliance on PARP for metabolic viability, the combination of ATRi and PARPi induced synthetic lethality in cervical cancer in vitro, and reduced tumor burden in vivo.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Gynecologic oncology
Gynecologic oncology 医学-妇产科学
CiteScore
8.60
自引率
6.40%
发文量
1062
审稿时长
37 days
期刊介绍: Gynecologic Oncology, an international journal, is devoted to the publication of clinical and investigative articles that concern tumors of the female reproductive tract. Investigations relating to the etiology, diagnosis, and treatment of female cancers, as well as research from any of the disciplines related to this field of interest, are published. Research Areas Include: • Cell and molecular biology • Chemotherapy • Cytology • Endocrinology • Epidemiology • Genetics • Gynecologic surgery • Immunology • Pathology • Radiotherapy
期刊最新文献
Evolutionary pathways in early-stage, non-myoinvasive endometrioid endometrial cancers of no specific molecular profile What happens after menopause? (WHAM): Impact of risk-reducing salpingo-oophorectomy on depressive and anxiety symptoms at 24 months KRAS mutations in endometrial cancers: Possible prognostic and treatment implications Too much of a good thing? Projecting the need for gynecologic oncologists over the next 20 years Disparities in ovarian cancer survival among ethnic Asian American populations, 2006–2020
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1