Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Street, Hefei, Anhui, 230032, People's Republic of China.
Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
BMC Cancer. 2022 Jun 8;22(1):628. doi: 10.1186/s12885-022-09699-7.
Eukaryotic translation elongation factors 1 δ (EEF1D), has garnered much attention with regards to their role in the drug resistance of cancers. In this paper, we investigated the effects and mechanisms of increasing the sensitivity of ovarian cancer cells to cisplatin or cis-dichlorodiammine platinum (DDP) by knockdown and knockout of EEF1D gene in cellular and animal models.
The EEF1D gene was knocked-down or -out by siRNA or CRISPR/Cas9 respectively in human ovarian cancer cell SKOV3, DDP-resistant subline SKOV3/DDP, and EEF1D gene in human primary ovarian cancer cell from 5 ovarian cancer patients with progressive disease/stable disease (PD/SD) was transiently knocked down by siRNA interference. The mice model bearing xenografted tumor was established with subcutaneous inoculation of SKOV3/DDP.
The results show that reducing or removing EEF1D gene expression significantly increased the sensitivity of human ovarian cancer cells to DDP in inhibiting viability and inducing apoptosis in vitro and in vivo, and also boosted DDP to inhibit xenografted tumor growth. Interfering with EEF1D gene expression in mice xenografted tumor significantly affected the levels of OPTN, p-Akt, Bcl-2, Bax, cleaved caspase-3 and ERCC1 compared to DDP treated mice alone, and had less effect on PI3K, Akt and caspase-3.
The knocking down or out EEF1D gene expression could enhance the sensitivity of ovarian cancer cells to DDP partially, which may be achieved via inactivating the PI3K/AKT signaling pathway, thus inducing cell apoptosis and decreasing repairment of DNA damage. Our study provides a novel therapeutic strategy for the treatment of ovarian cancer.
真核翻译延伸因子 1 δ（EEF1D）因其在癌症耐药性中的作用而备受关注。在本文中，我们在细胞和动物模型中研究了敲低和敲除 EEF1D 基因对顺铂或顺式二氯二氨合铂（DDP）敏感性的影响及其机制。
分别用 siRNA 或 CRISPR/Cas9 敲低或敲除人卵巢癌细胞 SKOV3、DDP 耐药亚系 SKOV3/DDP 中的 EEF1D 基因，以及 5 例进展期/稳定期（PD/SD）卵巢癌患者的人原代卵巢癌细胞中 EEF1D 基因，通过 siRNA 干扰瞬时敲低。用人卵巢癌细胞 SKOV3/DDP 皮下接种建立异种移植瘤小鼠模型。
结果表明，体外和体内降低或去除 EEF1D 基因表达显著增加了人卵巢癌细胞对 DDP 的敏感性，抑制了细胞活力并诱导了细胞凋亡，还增强了 DDP 抑制异种移植瘤生长的作用。与单独用 DDP 处理的小鼠相比，干扰小鼠异种移植瘤中的 EEF1D 基因表达对 OPTN、p-Akt、Bcl-2、Bax、cleaved caspase-3 和 ERCC1 的水平有显著影响，而对 PI3K、Akt 和 caspase-3 的影响较小。
敲低或敲除 EEF1D 基因表达可部分增强卵巢癌细胞对 DDP 的敏感性，这可能是通过使 PI3K/AKT 信号通路失活，从而诱导细胞凋亡和减少 DNA 损伤修复来实现的。我们的研究为卵巢癌的治疗提供了一种新的治疗策略。
