RIP1 promotes proliferation through G2/M checkpoint progression and mediates cisplatin-induced apoptosis and necroptosis in human ovarian cancer cells.
RIP1 promotes proliferation through G2/M checkpoint progression and mediates cisplatin-induced apoptosis and necroptosis in human ovarian cancer cells.
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RIP1 通过 G2/M 检查点进展促进增殖并介导顺铂诱导的人卵巢癌细胞凋亡和坏死性凋亡
DOI：
10.1038/s41401-019-0340-7
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发表时间：
2020-09
影响因子：
8.2
通讯作者：
Lin Y
中科院分区：
文献类型：
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作者：
Zheng XL;Yang JJ;Wang YY;Li Q;Song YP;Su M;Li JK;Zhang L;Li ZP;Zhou B;Lin Y
受体相互作用蛋白1（RIP 1，也称为RIPK 1）不仅是几种癌症中的肿瘤促进因子，而且在某些情况下介导细胞凋亡或坏死性凋亡。在这项研究中，我们研究了RIP 1在人类卵巢癌细胞中发挥的作用。我们发现，敲除（KO）的RIP 1基本上抑制细胞增殖，伴随着G2/M检查点阻滞在两个人卵巢癌细胞系SKOV 3和A2780。另一方面，RIP 1 KO显著减弱顺铂诱导的细胞毒性，这与凋亡标志物PARP切割和坏死性凋亡标志物磷酸化MLKL的减少有关。我们发现，RIP 1 KO抑制顺铂诱导的ROS在SKOV 3和A2780细胞中的积累。ROS清除剂BHA、凋亡抑制剂Z-VAD或坏死性凋亡抑制剂NSA均能有效抑制顺铂对对照细胞的毒性作用，提示ROS介导的凋亡和坏死性凋亡参与了顺铂诱导的细胞死亡。此外，用MLKL siRNA阻断坏死性凋亡有效地减弱了顺铂诱导的细胞毒性。在人卵巢癌A2780细胞系裸鼠移植瘤中，RIP 1 KO不仅显著抑制肿瘤生长，而且显著减弱顺铂的抗癌活性。我们的研究结果表明RIP 1在人类卵巢癌中具有双重作用：它既可以作为肿瘤促进因子促进癌细胞增殖，也可以作为肿瘤抑制因子促进顺铂等化疗药物的抗癌作用。
Receptor-interacting protein 1 (RIP1, also known as RIPK1) is not only a tumor-promoting factor in several cancers but also mediates either apoptosis or necroptosis in certain circumstances. In this study we investigated what role RIP1 plays in human ovarian cancer cells. We showed that knockout (KO) of RIP1 substantially suppressed cell proliferation, accompanied by the G2/M checkpoint arrest in two human ovarian cancer cell lines SKOV3 and A2780. On the other hand, RIP1 KO remarkably attenuated cisplatin-induced cytotoxicity, which was associated with reduction of the apoptosis markers PARP cleavage and the necroptosis marker phospho-MLKL. We found that RIP1 KO suppressed cisplatin-induced ROS accumulation in both SKOV3 and A2780 cells. ROS scavenger BHA, apoptosis inhibitor Z-VAD or necroptosis inhibitor NSA could effectively suppress cisplatin’s cytotoxicity in the control cells, suggesting that ROS-mediated apoptosis and necroptosis were involved in cisplatin-induced cell death. In addition, blocking necroptosis with MLKL siRNA effectively attenuated cisplatin-induced cytotoxicity. In human ovarian cancer A2780 cell line xenograft nude mice, RIP1 KO not only significantly suppressed the tumor growth but also greatly attenuated cisplatin’s anticancer activity. Our results demonstrate a dual role of RIP1 in human ovarian cancer: it acts as either a tumor-promoting factor to promote cancer cell proliferation or a tumor-suppressing factor to facilitate anticancer effects of chemotherapeutics such as cisplatin.
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影响因子：
5.3
作者：
Lin, Y;Devin, A;Liu, ZG
通讯作者：
Liu, ZG
影响因子：
4.4
作者：
Kaiser, WJ;Offermann, MK
通讯作者：
Offermann, MK
影响因子：
10.5
作者：
Hur, GM;Lewis, J;Liu, ZG
通讯作者：
Liu, ZG
影响因子：
10.5
作者：
Lin, Y;Devin, A;Liu, ZG
通讯作者：
Liu, ZG
影响因子：
8
作者：
通讯作者：
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