Hsp90 inhibitor 17-AAG inhibits stem cell-like properties and chemoresistance in osteosarcoma cells via the Hedgehog signaling pathway
Hsp90 inhibitor 17-AAG inhibits stem cell-like properties and chemoresistance in osteosarcoma cells via the Hedgehog signaling pathway
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DOI：
10.3892/or.2020.7597
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发表时间：
2020-07-01
期刊：
影响因子：
4.2
通讯作者：
Ran, Yuliang
中科院分区：
文献类型：
--
作者：
Shu, Xiong;Liu, Huiqi;Ran, Yuliang
多重耐药是骨肉瘤（OS）成功治疗的主要障碍。最近的研究表明，一种被称为OS干细胞（OSCs）的细胞亚群在获得多重耐药的过程中起着至关重要的作用。因此，需要更好地了解OS的生物学和发病机制，以推进靶向治疗的发展，旨在根除这一特定的细胞亚群，以逆转OS的获得性化疗耐药。本研究的目的是评估17-AAG的抗osc作用，并确定其潜在的分子机制。发现热休克蛋白90在肌球细胞中的表达增加，并与癌症干细胞特征呈正相关。此外，17-AAG能够抑制OS细胞的干细胞样表型。机制上，17-AAG通过糖原合成酶激酶（GSK） 3 β失活介导的刺猬信号通路抑制osc样特性和化学耐药。本研究结果为17-AAG通过抑制GSK3 β /Hedgehog信号通路抑制OSC性质和化疗耐药提供了全面证据，提示17-AAG可能是一种有前景的靶向OSC治疗药物。
Multiple drug resistance is a major obstacle to the successful treatment of osteosarcoma (OS). Recent studies have demonstrated that a subset of cells, referred to as OS stem cells (OSCs), play a crucial role in the acquisition of multiple drug resistance. Therefore, an improved understanding of OS biology and pathogenesis is required to advance the development of targeted therapies aimed at eradicating this particular subset of cells in order to reverse acquired chemoresistance in OS. The aim of the present study was to assess the anti-OSC effects of 17-AAG and determine the underlying molecular mechanism. Heat shock protein 90 expression was found to be increased in sarcosphere cells and was positively associated with cancer stem cell characteristics. In addition, 17-AAG was able to suppress the stem cell-like phenotype of OS cells. Mechanistically, 17-AAG inhibited OSC-like properties and chemoresistance through glycogen synthase kinase (GSK) 3 beta inactivation-mediated repression of the Hedgehog signaling pathway. The findings of the present study provided comprehensive evidence for the inhibition of OSC properties and chemoresistance by 17-AAG through repression of the GSK3 beta/Hedgehog signaling pathway, suggesting that 17-AAG may be a promising therapeutic agent for targeting OSCs.