Department of Ophthalmology, Shengjing Hospital of China Medical University, Shengyang, Liaoning, China.
Department of Ophthalmology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China.
J Cell Physiol. 2021 Mar;236(3):2214-2225. doi: 10.1002/jcp.30010. Epub 2020 Aug 11.
Retinoblastoma is the most common intraocular cancer with metastatic potential affecting infants and children. Although chemotherapy is available for retinoblastoma, side effects and drug resistance are frequent. Rpl41, encoding ribosomal protein L41 (RPL41), has been identified as a tumor suppressor gene, and its targeted degradation of activating transcription factor 4 (ATF4) produces an antitumor effect. The goal of the present study is to provide experimental evidence for the clinical application of a small peptide regimen in combination with chemotherapy for the treatment of retinoblastoma and to investigate the mechanism of their combined cytotoxicity. It was observed that treatment with the RPL41 peptide alone decreased the viability, migration, and invasion of retinoblastoma Y79 and Weri-Rb1 cells, in addition to promoting cell apoptosis and cell cycle arrest. Furthermore, RPL41 protein levels showed a significantly decreased trend in retinoblastoma specimens, whereas ATF4 protein levels tended to be increased. Mechanistically, ATF4 degradation as a result of RPL41 peptide treatment was observed in retinoblastoma Y79 and Weri-Rb1 cells. Most important, low-dose administration of the RPL41 peptide significantly enhanced the antitumor effect of carboplatin, and further analysis confirmed their synergistic effect as anti-retinoblastoma therapy, indicating that RPL41 sensitized Y79 and Weri-Rb1 retinoblastoma cells to carboplatin. Thus, our data provide a preclinical rationale for the exploration of the RPL41 peptide as a potential adjuvant to carboplatin treatment in retinoblastoma.
视网膜母细胞瘤是最常见的具有转移潜能的眼内癌，影响婴儿和儿童。尽管有化疗可用于治疗视网膜母细胞瘤，但副作用和耐药性很常见。编码核糖体蛋白 L41（RPL41）的 Rpl41 已被确定为肿瘤抑制基因，其靶向降解激活转录因子 4（ATF4）产生抗肿瘤作用。本研究的目的是为小肽方案联合化疗治疗视网膜母细胞瘤的临床应用提供实验依据，并探讨它们联合细胞毒性的机制。结果表明，单独使用 RPL41 肽处理可降低视网膜母细胞瘤 Y79 和 Weri-Rb1 细胞的活力、迁移和侵袭能力，促进细胞凋亡和细胞周期停滞。此外，视网膜母细胞瘤标本中 RPL41 蛋白水平呈显著下降趋势，而 ATF4 蛋白水平呈上升趋势。从机制上讲，在视网膜母细胞瘤 Y79 和 Weri-Rb1 细胞中观察到 RPL41 肽处理导致 ATF4 降解。最重要的是，RPL41 肽的低剂量给药显著增强了卡铂的抗肿瘤作用，进一步分析证实了它们作为抗视网膜母细胞瘤治疗的协同作用，表明 RPL41 使 Y79 和 Weri-Rb1 视网膜母细胞瘤细胞对卡铂敏感。因此，我们的数据为探索 RPL41 肽作为卡铂治疗视网膜母细胞瘤的潜在辅助剂提供了临床前依据。
