靶向 AKT 是治疗 SOX2 阳性、化疗耐药骨肉瘤的有效策略

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING
Yujie Liu, Li Kang, Jing Luo, Minglei Yang, Da Wang, Juelan Ye, Xinghai Yang, Wei Wan, Jiemin Wong, Jianru Xiao
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引用次数: 0

摘要

骨肉瘤(OS)是最常见的原发性恶性骨癌,目前缺乏有效的靶向治疗。越来越多的证据表明,SOX2过表达是OS的主要驱动因素。通过筛选一个小分子激酶抑制剂文库,我们发现AKT是OS细胞中SOX2强劲表达所必需的激酶。AKT在OS中频繁过表达,且与SOX2蛋白水平呈正相关。我们证明AKT对SOX2转录没有影响,但促进SOX2蛋白的稳定性。在机制上,AKT在T116位点结合并磷酸化SOX2,通过泛素E3连接酶UBR5和STUB1阻止SOX2泛素化和蛋白酶体依赖性降解。此外,我们发现AKT- sox2轴是肿瘤干细胞和化疗耐药的重要调节剂,AKT抑制剂MK2206和顺铂联合使用可协同有效抑制PDX模型中OS肿瘤的生长。总之,我们发现AKT在OS中促进SOX2过表达、肿瘤干性和化疗耐药中发挥关键作用,并提供证据表明靶向AKT联合化疗可能有望治疗难治性OS。工作模型显示AKT通过磷酸化T116位点来稳定SOX2。AKT的磷酸化抑制了UBR5和STUB1对SOX2的结合和泛素化,从而促进了SOX2的稳定性和致瘤活性。MK2206靶向AKT抑制T116磷酸化,促进SOX2泛素化通路,从而削弱SOX2的致瘤活性。化疗试剂联合AKT抑制剂治疗sox2阳性OS效果较好。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Targeting AKT as a promising strategy for SOX2-positive, chemoresistant osteosarcoma

Targeting AKT as a promising strategy for SOX2-positive, chemoresistant osteosarcoma

Osteosarcoma (OS) is the most prevalent type of primary malignant bone cancer and currently lacks effective targeted treatments. Increasing evidence indicates that SOX2 overexpression is a primary driver of OS. By screening a small-molecule kinase inhibitor library, we identified AKT as a kinase essential for robust SOX2 expression in OS cells. AKT was found to be frequently overexpressed in OS and positively correlated with SOX2 protein levels. We demonstrated that AKT has no effect on SOX2 transcription but promotes SOX2 protein stability. Mechanistically, AKT binds to and phosphorylates SOX2 at T116, preventing SOX2 ubiquitination and proteasome-dependent degradation by ubiquitin E3 ligases UBR5 and STUB1. Moreover, we found that AKT-SOX2 axis is a significant modulator of cancer stemness and chemoresistance and that the combination of AKT inhibitor MK2206 and cisplatin resulted in a synergistic and potent inhibition of OS tumor growth in the PDX model. In conclusion, we identified a critical role for AKT in promoting SOX2 overexpression, tumor stemness, and chemoresistance in OS, and provided evidence that targeting AKT combined with chemotherapy may hold promise for treating refractory OS.

Working model showing that AKT stabilizes SOX2 by phosphorylating T116 site. Phosphorylation by AKT restraints the binding and ubiquitinoylation of SOX2 by the UBR5 and STUB1, thus promoting SOX2 stability and tumorigenic activity. Targeting AKT by MK2206 inhibits T116 phosphorylation and promotes SOX2 ubiquitination pathway, which impairs SOX2 tumorigenic activity. A combined treatment with chemo reagent and AKT inhibitor could achieve better therapeutic effect for SOX2-positive OS.

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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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