UBE2K Facilitates Erlotinib Resistance and Induces Epithelial Mesenchymal Transition in Osteosarcoma Cancer Stem-Like Cells via Activating the mTOR Signaling.

IF 2.9 4区医学 Q2 PHARMACOLOGY & PHARMACY

Pharmacology Pub Date : 2025-03-28 DOI:10.1159/000545370

Tian Wang, Lian Zhang, Qi Liu, Dexing Wang, Ping Yang

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引用次数: 0

Abstract

Introduction: Osteosarcoma (OS) is an aggressive bone tumor, and EGFR inhibitors are commonly used as targeted drugs for OS treatment. Herein, roles of ubiquitin-conjugating enzyme E2K (UBE2K) in EGFR inhibitor resistance of OS were studied.

Methods: CD133+ MG63 and CD133+ U2OS cells were isolated using sorting flow cytometry and defined as osteosarcoma stem cells (OSCs)-MG63 and OSCs-U2OS, respectively. The stemness in MG63 and U2OS cells was evaluated by sphere formation assay. Cell activity, apoptosis, and migration were appraised using CCK-8 assay, TUNEL staining, and wound healing assay. Western blotting was used to detect the expression of related proteins.

Results: OSCs-MG63 and OSCs-U2OS cells showed erlotinib resistant and high expression of UBE2K. Knocking down UBE2K reversed the erlotinib resistance, declined migration rate, and inhibited mitochondrial biogenesis in OSCs-MG63 and OSCs-U2OS cells. Silencing UBE2K inhibited the stemness in MG63 and U2OS cells, accompanied by reduced CD133+ cell proportion and restrained sphere formation ability. Silencing UBE2K repressed the mTOR/4EBP1/Cyclin D1/p21 signaling pathway in OSCs-MG63 and OSCs-U2OS cells. Furthermore, the influence of UBE2K silencing on the stemness of MG63 cells and the epithelial-mesenchymal transition (EMT) progression in OSCs-MG63 cells was partially abolished by MHY1485, an agonist of mTOR signaling.

Conclusion: UBE2K facilitated the erlotinib resistance and induced EMT in OSCs via regulating the mTOR signaling.

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UBE2K通过激活mTOR信号通路促进厄洛替尼耐药，诱导骨肉瘤癌干细胞样细胞上皮间充质转化。

骨肉瘤（Osteosarcoma， OS）是一种侵袭性骨肿瘤，EGFR抑制剂常被用作骨肉瘤治疗的靶向药物。本文研究了泛素偶联酶E2K （UBE2K）在OS对EGFR抑制剂耐药性中的作用。方法：采用分选流式细胞术分离CD133+ MG63和CD133+ U2OS细胞，分别定义为骨肉瘤干细胞(OSCs)-MG63和OSCs-U2OS。用成球法评价MG63和U2OS细胞的干性。采用CCK-8法、TUNEL染色法和伤口愈合法评价细胞活性、凋亡和迁移。Western blotting检测相关蛋白的表达。结果：OSCs-MG63和OSCs-U2OS细胞对厄洛替尼耐药，UBE2K高表达。敲除UBE2K可逆转厄洛替尼耐药性，降低迁移率，抑制OSCs-MG63和OSCs-U2OS细胞的线粒体生物发生。沉默UBE2K抑制了MG63和U2OS细胞的干性，同时CD133+细胞比例降低，球体形成能力受到抑制。沉默UBE2K可抑制OSCs-MG63和OSCs-U2OS细胞的mTOR/4EBP1/Cyclin D1/p21信号通路。此外，UBE2K沉默对MG63细胞的干性和OSCs-MG63细胞的EMT进展的影响被mTOR信号激动剂MHY1485部分消除。结论：UBE2K通过调控mTOR信号通路促进osc对厄洛替尼的耐药，诱导EMT。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmacology 医学-药学

CiteScore

5.60

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： ''Pharmacology'' is an international forum to present and discuss current perspectives in drug research. The journal communicates research in basic and clinical pharmacology and related fields. It covers biochemical pharmacology, molecular pharmacology, immunopharmacology, drug metabolism, pharmacogenetics, analytical toxicology, neuropsychopharmacology, pharmacokinetics and clinical pharmacology. In addition to original papers and short communications of investigative findings and pharmacological profiles the journal contains reviews, comments and perspective notes; research communications of novel therapeutic agents are encouraged.