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首页> 外文期刊>The Journal of toxicological sciences >shRNA-mediated AMBRA1 knockdown reduces the cisplatin-induced autophagy and sensitizes ovarian cancer cells to cisplatin
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shRNA-mediated AMBRA1 knockdown reduces the cisplatin-induced autophagy and sensitizes ovarian cancer cells to cisplatin

机译：shRNA介导的AMBRA1敲低可减少顺铂诱导的自噬，并使卵巢癌细胞对顺铂敏感

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Recent research has revealed a role for Ambra1, an autophagy-related gene-related (ATG) protein, in the autophagic pro-survival response, and Ambra1 has been shown to regulate Beclin1 and Beclin1-dependent autophagy in embryonic stem cells and cancer cells. However, whether Ambra1 plays an important role in the autophagy pathway in ovarian cancer cells is unknown. In this study, we hypothesized that Ambra1 is an important regulator of autophagy and apoptosis in ovarian cancer cells. We firstly confirmed autophagic activity in ovarian cancer OVCAR-3 cells which were treated with cisplatin by assessing endogenous microtubule-associated protein 1 light chain 3 (LC3) localization and the presence of autophagosomes and LC3 protein levels in OVCAR-3 cells. Cell apoptosis and viability were measured by annexin-V and PI staining and MTT assays. We then knocked down Ambra1 expression with transfection with the plasmid expressing the small hairpin RNA (shRNA) targeting AMBRA1, then re-evaluated autophagy in the OVCAR-3 cells subject to cisplatin treatment, and re-determined the sensitivity of OVCAR-3 cells to cisplatin. Results demonstrated that cisplatin treatment induced autophagy in OVCAR-3 cells in association with Ambra1 upregulation in the ovarian cancer cells. When Ambra1 expression was reduced by shRNA, the ovarian cancer cells were more sensitive to cisplatin. In conclusion, Ambra1 is a crucial regulator of autophagy and apoptosis in ovarian cancer cells subject to cisplatin to maintain the balance between autophagy and apoptosis. And the Ambra1-targeting inhibition might be an effective method to sensitize ovarian cancer cells to chemotherapy.
机译：最近的研究表明，自噬相关基因相关（ATG）蛋白Ambra1在自噬生存前应答中的作用，并且已证明Ambra1在胚胎干细胞和癌细胞中调节Beclin1和Beclin1依赖性自噬。但是，尚不清楚Ambra1是否在卵巢癌细胞的自噬途径中起重要作用。在这项研究中，我们假设Ambra1是卵巢癌细胞自噬和凋亡的重要调节剂。我们首先通过评估内源性微管相关蛋白1轻链3（LC3）的定位以及OVCAR-3细胞中自噬体和LC3蛋白水平的存在，证实了用顺铂治疗的卵巢癌OVCAR-3细胞的自噬活性。通过膜联蛋白-V和PI染色以及MTT测定法测量细胞凋亡和生存力。然后，我们用表达靶向AMBRA1的小发夹RNA（shRNA）的质粒转染来降低Ambra1的表达，然后重新评估接受顺铂处理的OVCAR-3细胞的自噬，并重新确定OVCAR-3细胞对顺铂。结果表明，顺铂治疗可诱导OVCAR-3细胞自噬，并与卵巢癌细胞中的Ambra1上调相关。当shRNA降低Ambra1表达时，卵巢癌细胞对顺铂更加敏感。总之，Ambra1是顺铂治疗卵巢癌细胞中自噬和凋亡的重要调节剂，以维持自噬和凋亡之间的平衡。而且靶向Ambra1的抑制作用可能是使卵巢癌细胞对化疗敏感的有效方法。

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