The First Clinical College, Hubei University of Chinese Medicine, Wuhan, Hubei, China.
Department of Medicine, Yangtze University, Jingzhou, Hubei Province, China.
Biochem Biophys Res Commun. 2019 Mar 19;510(4):580-586. doi: 10.1016/j.bbrc.2019.01.117. Epub 2019 Feb 7.
The essential roles of eukaryotic translation initiation factor 4E (eIF4E) have been shown in various cancers, including ovarian cancer. In this work, we demonstrate that eIF4E inhibition in ovarian cancer can be achieved by ribavirin, a FDA-approved antiviral drug. We show that ribavirin at clinically relevant doses significantly inhibits growth and survival in multiple ovarian cancer cell lines, regardless of morphological and molecular subtypes. Mechanistically, ribavirin suppresses Akt/mTOR and eIF4E/p70S6K signaling pathways in ovarian cancer cells. We confirm that eIF4E is the critical molecular target of ribavirin, and furthermore that this is dependent on phosphorylation at S209. Notably, using both in vitro cell culture system and in vivo xenograft mouse model, we show that the combination of ribavirin with cisplatin (standard of care for patients with ovarian cancer) results in significantly greater efficacy than cisplatin alone in ovarian cancer. Interestingly, the sensitivity to ribavirin varies among a panel of ovarian cancer cell lines, mostly likely due to their differential expression level of eIF4E and dependency to eIF4E inhibition. The differential expression level is further observed in ovarian cancer tissues, with the higher level of eIF4E in the majority of ovarian cancer tissues compared to normal ovary tissues. Our work suggests that eIF4E expression varies among ovarian cancer. Additionally, ribavirin is a useful addition to ovarian cancer treatment, particularly to those with high dependency on eIF4E.
真核翻译起始因子 4E（eIF4E）的基本作用已在多种癌症中得到证实，包括卵巢癌。在这项工作中，我们证明了利巴韦林，一种 FDA 批准的抗病毒药物，可以抑制卵巢癌细胞中的 eIF4E。我们表明，利巴韦林在临床相关剂量下，可显著抑制多种卵巢癌细胞系的生长和存活，而与形态和分子亚型无关。在机制上，利巴韦林抑制卵巢癌细胞中的 Akt/mTOR 和 eIF4E/p70S6K 信号通路。我们证实 eIF4E 是利巴韦林的关键分子靶标，并且进一步证实这依赖于 S209 的磷酸化。值得注意的是，我们使用体外细胞培养系统和体内异种移植小鼠模型，表明利巴韦林与顺铂（卵巢癌患者的标准治疗方法）联合使用在卵巢癌中的疗效明显优于顺铂单独使用。有趣的是，一组卵巢癌细胞系对利巴韦林的敏感性不同，这很可能是由于它们的 eIF4E 表达水平不同和对 eIF4E 抑制的依赖性不同。在卵巢癌组织中也观察到了这种差异表达水平，与正常卵巢组织相比，大多数卵巢癌组织中的 eIF4E 水平更高。我们的工作表明 eIF4E 在卵巢癌中存在表达差异。此外，利巴韦林是卵巢癌治疗的有用补充，特别是对那些对 eIF4E 依赖性高的患者。
