U1 snRNP复合体调节剂APT20TTMG在胶质母细胞瘤模型中的作用

IF 3.5 4区 医学 Q2 ONCOLOGY
Caio Bruno Quinta de Souza Leal, Camila Guimarães Moreira Zimmer, Vanessa de Vasconcelos Castilho Sinatti, Ericks Sousa Soares, Michael S Rafii, Rafael Mantovani Bottos
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引用次数: 0

摘要

U1小核核糖核蛋白(snRNP)复合物对于mrna前剪接和抑制过早聚腺苷化至关重要。它的功能障碍涉及多种癌症,包括胶质母细胞瘤,驱动致癌剪接和肿瘤进展。本研究探索了APT20TTMG(一种调节U1 snRNP错组装的合成cDNA)在胶质母细胞瘤中的潜力。在U-87 MG细胞中评估APT20TTMG的内化,以及其对细胞活力、增殖和凋亡的影响。采用胸腺小鼠评价静脉给药APT20TTMG对肿瘤相关参数的影响。APT20TTMG在体外具有50%以上的内化作用,具有细胞毒、细胞抑制和促凋亡作用。用APT20TTMG治疗22天,肿瘤体积减小,肿瘤生长减慢,并有体重增加的趋势。治疗也减少了致癌途径,并倾向于提高组织病理学结果。一项将APT20TTMG联合替莫唑胺的初步研究进一步提高了抗肿瘤疗效。我们的研究结果表明,APT20TTMG在纠正U1 snRNP复合物功能障碍方面具有很强的潜力,支持其作为调节胶质母细胞瘤剪接策略的进一步研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Effects of APT20TTMG, a modulator of the U1 snRNP complex, in glioblastoma models.

The U1 small nuclear ribonucleoprotein (snRNP) complex is essential for pre-mRNA splicing and inhibition of premature polyadenylation. Its dysfunction has been implicated in various cancers, including glioblastoma, driving oncogenic splicing and tumor progression. This study explored the potential of APT20TTMG, a synthetic cDNA that modulates U1 snRNP misassembly, in glioblastoma. The internalization of APT20TTMG was assessed in U-87 MG cells, as well as its effects on cell viability, proliferation, and apoptosis. Athymic mice were used to evaluate the effects of intravenous APT20TTMG administration on tumor-related parameters. APT20TTMG exhibited over 50% internalization, exerting cytotoxic, cytostatic, and pro-apoptotic effects in vitro. A 22-day treatment with APT20TTMG reduced tumor volume, slowed tumor growth, and showed a trend toward increased body weight. Treatment also decreased oncogenic pathways and tended to enhance histopathological outcomes. A pilot study combining APT20TTMG with temozolomide further improved antitumor efficacy. Our results demonstrate that APT20TTMG has strong potential in correcting U1 snRNP complex dysfunction, supporting its further investigation as a strategy to modulate splicing in glioblastoma.

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来源期刊
Medical Oncology
Medical Oncology 医学-肿瘤学
CiteScore
4.20
自引率
2.90%
发文量
259
审稿时长
1.4 months
期刊介绍: Medical Oncology (MO) communicates the results of clinical and experimental research in oncology and hematology, particularly experimental therapeutics within the fields of immunotherapy and chemotherapy. It also provides state-of-the-art reviews on clinical and experimental therapies. Topics covered include immunobiology, pathogenesis, and treatment of malignant tumors.
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