Department of Pharmacology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, People's Republic of China.
Department of Pathology, First Hospital, Lanzhou University, Lanzhou 730000, People's Republic of China.
Toxicol Appl Pharmacol. 2021 Mar 15;415:115450. doi: 10.1016/j.taap.2021.115450. Epub 2021 Feb 9.
Eukaryotic translation initiation factor 4E (eIF4E) and protein arginine methyltransferase 5 (PRMT5) are frequently overexpressed in colorectal cancer (CRC) tissues and associated with poor prognosis. Ribavirin, the only clinically approved drug known to target eIF4E, is an anti-viral molecule currently used in hepatitis C therapy. The potential of ribavirin to treat CRC remains largely unknown. Ribavirin treatment in CRC cell lines drastically inhibited cell proliferation and colony formation, induced S phase arrest and reduced cyclin D1, cyclin A/E and proliferating cell nuclear antigen (PCNA) levels in vitro, and suppressed tumorigenesis in mouse model of colitis-associated CRC. Mechanistically, ribavirin treatment significantly reduced PRMT5 and eIF4E protein levels and the accumulation of symmetric dimethylation of histone 3 at arginine 8 (H3R8me2s) and that of histone 4 at arginine 3 (H4R3me2s). Importantly, inhibition of PRMT5 by ribavirin resulted in promoted H3R8 methylation in eIF4E promoter region. Our results demonstrate the anti-cancer efficacy of ribavirin in CRC and suggest that the anti-cancer efficacy of ribavirin may be mediated by downregulating PRMT5 levels but not its enzymatic activity.
真核翻译起始因子 4E（eIF4E）和精氨酸甲基转移酶 5（PRMT5）在结直肠癌（CRC）组织中经常过表达，并与预后不良相关。利巴韦林是唯一一种已知靶向 eIF4E 的临床批准药物，是一种抗病毒分子，目前用于丙型肝炎治疗。利巴韦林治疗 CRC 的潜力在很大程度上仍不清楚。利巴韦林在 CRC 细胞系中的治疗可显著抑制细胞增殖和集落形成，体外诱导 S 期停滞并降低细胞周期蛋白 D1、细胞周期蛋白 A/E 和增殖细胞核抗原（PCNA）水平，并抑制结肠炎相关 CRC 的小鼠模型中的肿瘤发生。在机制上，利巴韦林治疗可显著降低 PRMT5 和 eIF4E 蛋白水平，以及组蛋白 3 第 8 位精氨酸（H3R8me2s）和组蛋白 4 第 3 位精氨酸（H4R3me2s）的对称二甲基化的积累。重要的是，利巴韦林对 PRMT5 的抑制作用导致 eIF4E 启动子区域的 H3R8 甲基化增加。我们的研究结果证明了利巴韦林在 CRC 中的抗癌疗效，并表明利巴韦林的抗癌疗效可能是通过下调 PRMT5 水平而不是其酶活性来介导的。
