| 黄 裕,王 冬,顾荣花.ONC206 抑制浆液性乳头状子宫内膜癌增殖和转移的体外研究[J].肿瘤学杂志,2020,26(9):796-802. |
| ONC206 抑制浆液性乳头状子宫内膜癌增殖和转移的体外研究 |
| ONC206 Exhibits Anti-Proliferative and Anti-Metastatic via Activation of Integrated Stress Response in Uterine Papillary Serous Carcinoma in vitro |
| 投稿时间：2020-02-02 |
| DOI：10.11735/j.issn.1671-170X.2020.09.B009 |
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| 中文关键词: ONC206 子宫内膜癌 侵袭转移 凋亡 整合应激反应 |
| 英文关键词:ONC206 endometrial cancer invasion and metastasis apoptosis integrated stress response |
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| 中文摘要: |
| 摘 要：［目的］ 探讨ONC206对子宫浆液性乳头状腺癌（UPSC）细胞系增殖、粘附和侵袭的作用，评估其抗肿瘤效能，并分析其机制。［方法］ 用ONC201或ONC206治疗UPSC细胞系ARK1和SPEC2，MTT法和半胱天冬酶-3、9（Caspase-3，9）测定检测细胞增殖和凋亡，并进行粘附实验、伤口愈合实验量化其降低转移和侵袭的能力，进行活性氧（ROS）和JC-1检测，分析整合应激反应（ISR）。使用整合应激抑制剂N-乙酰半胱氨酸预处理后，重复进行ONC206的增殖，侵袭和应激测定，蛋白质印迹法检测相应蛋白表达水平。［结果］ 在UPSC细胞系ARK1和SPEC2中，ONC206以浓度依赖方式抑制其增殖，平均IC50值分别为330nM和240nM，均低于ONC201。Caspase-3、9表达水平升高，ROS与基线相比增加83%~105％，线粒体膜电位降低16%~38％，ISR特异性蛋白表达增加，上皮-间质转化蛋白表达下调。使用NAC后，ONC206对肿瘤细胞黏附、增殖和侵袭的抑制功效降低。［结论］ 亚吡哌酮家族药物ONC206通过肿瘤坏死因子相关凋亡诱导配体（TRAIL）介导的凋亡途径，同时激活ISR传播下游效应，降低UPSC肿瘤细胞的增殖、粘附和侵袭能力。 |
| 英文摘要: |
| Abstract：［Objective］ To investigate the anti-tumorigenic effects of ONC206 on the proliferation，adhesion，and invasion of uterine papillary serous carcinoma(UPSC) cell lines，as well as elucidate its mechanisms of action. ［Methods］ UPSC cell lines ARK1 and SPEC2 were treated with either ONC201 or ONC206，cellular proliferation and apoptosis were measured by using MTT and caspase-3/9 assays. In vitro wound healing assay and adhesion test were performed to quantify metastatic and invasive potential，performed reactive oxygen species(ROS) and JC-1 detection，and analyze the integrated stress response(ISR). Proliferation，invasion，and stress assays were repeated after pretreatment of stress inhibitor N-acetylcysteine(NAC). Western blots were run to assess target protein expression levels. ［Results］ In UPSC cell lines ARK1 and SPEC2，ONC206 inhibited its proliferation in a dose-dependent manner，with average IC50 of 330nM and 240nM，respectively，which were lower than ONC201. Caspase-3，9 expression levels increased，ROS increased 83%~105% compared to baseline，mitochondrial membrane potential decreased 16%~38%，ISR-specific protein expression increased，and epithelial-mesenchymal transition protein expression was down-regulated. Efficacy of ONC206 on adhesion，wound healing，and cellular proliferation were significantly decreased after pretreatment with NAC. ［Conclusion］ The piperidine family drug ONC206 through the TRAIL-mediated apoptosis pathway，and simultaneously activates the downstream effects of ISR transmission，which significantly reduces the proliferation，adhesion and invasion of UPSC tumor cells. |
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