Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.
Department of Physiology, McGill University, Montreal, Canada.
Sci Rep. 2021 Sep 16;11(1):18516. doi: 10.1038/s41598-021-97765-8.
Rocaglates are a class of eukaryotic translation initiation inhibitors that are being explored as chemotherapeutic agents. They function by targeting eukaryotic initiation factor (eIF) 4A, an RNA helicase critical for recruitment of the 40S ribosome (and associated factors) to mRNA templates. Rocaglates perturb eIF4A activity by imparting a gain-of-function activity to eIF4A and mediating clamping to RNA. To appreciate how rocaglates could best be enabled in the clinic, an understanding of resistance mechanisms is important, as this could inform on strategies to bypass such events as well as identify responsive tumor types. Here, we report on the results of a positive selection, ORFeome screen aimed at identifying cDNAs capable of conferring resistance to rocaglates. Two of the most potent modifiers of rocaglate response identified were the transcription factors FOXP3 and NR1I3, both of which have been implicated in ABCB1 regulation-the gene encoding P-glycoprotein (Pgp). Pgp has previously been implicated in conferring resistance to silvestrol, a naturally occurring rocaglate, and we show here that this extends to additional synthetic rocaglate derivatives. In addition, FOXP3 and NR1I3 impart a multi-drug resistant phenotype that is reversed upon inhibition of Pgp, suggesting a potential therapeutic combination strategy.
罗卡利特是一类真核翻译起始抑制剂，正被探索作为化疗药物。它们通过靶向真核起始因子（eIF）4A 发挥作用，eIF4A 是一种 RNA 解旋酶，对于将 40S 核糖体（和相关因子）募集到 mRNA 模板至关重要。罗卡利特通过赋予 eIF4A 功能获得活性并介导与 RNA 的钳夹来扰乱 eIF4A 活性。为了了解罗卡利特在临床上如何能得到最好的应用，了解耐药机制很重要，因为这可以为规避这些事件的策略提供信息，并确定对治疗有反应的肿瘤类型。在这里，我们报告了一项正向选择 ORFeome 筛选的结果，该筛选旨在鉴定能够赋予罗卡利特抗性的 cDNA。鉴定出的两种最有效的罗卡利特反应调节剂是转录因子 FOXP3 和 NR1I3，它们都与 ABCB1 调节有关——编码 P-糖蛋白（Pgp）的基因。Pgp 先前被认为与天然罗卡利特 silvestrol 的耐药性有关，我们在这里表明，这也扩展到其他合成罗卡利特衍生物。此外，FOXP3 和 NR1I3 赋予多药耐药表型，当抑制 Pgp 时会逆转，这表明可能存在一种治疗联合策略。
