一种异恶唑并醌衍生物通过靶向信号转导和转录激活因子3（STAT3）并触发其泛素依赖性降解来抑制肿瘤生长。
An Isoxazoloquinone Derivative Inhibits Tumor Growth by Targeting STAT3 and Triggering Its Ubiquitin-Dependent Degradation.
作者信息
Xie Yuanzhu, Zhu Shuaiwen, Chen Ling, Liu Hongdou, Peng Ting, Ming Zhengnan, Zou Zizheng, Hu Xiyuan, Luo Wensong, Peng Kunjian, Nie Yuan, Luo Tiao, Ma Dayou, Liu Suyou, Luo Zhiyong
机构信息
Department of Biochemistry and Molecular Biology, Hunan Province Key Laboratory of Basic and Applied Hematology, Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Xiangya School of Medicine, Central South University, Changsha 410008, China.
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China.
出版信息
Cancers (Basel). 2023 Apr 23;15(9):2424. doi: 10.3390/cancers15092424.
BACKGROUND
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with shorter five-year survival than other breast cancer subtypes, and lacks targeted and hormonal treatment strategies. The signal transducer and activator of transcription 3 (STAT3) signaling is up-regulated in various tumors, including TNBC, and plays a vital role in regulating the expression of multiple proliferation- and apoptosis-related genes.
RESULTS
By combining the unique structures of the natural compounds STA-21 and Aulosirazole with antitumor activities, we synthesized a class of novel isoxazoloquinone derivatives and showed that one of these compounds, ZSW, binds to the SH2 domain of STAT3, leading to decreased STAT3 expression and activation in TNBC cells. Furthermore, ZSW promotes STAT3 ubiquitination, inhibits the proliferation of TNBC cells in vitro, and attenuates tumor growth with manageable toxicities in vivo. ZSW also decreases the mammosphere formation of breast cancer stem cells (BCSCs) by inhibiting STAT3.
CONCLUSIONS
We conclude that the novel isoxazoloquinone ZSW may be developed as a cancer therapeutic because it targets STAT3, thereby inhibiting the stemness of cancer cells.
背景
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，其五年生存率低于其他乳腺癌亚型，且缺乏靶向和激素治疗策略。信号转导和转录激活因子3（STAT3）信号通路在包括TNBC在内的多种肿瘤中上调，并在调节多个增殖和凋亡相关基因的表达中起关键作用。
结果
通过将具有抗肿瘤活性的天然化合物STA - 21和环棱褐孔菌酸的独特结构相结合，我们合成了一类新型异恶唑并喹啉衍生物，并表明其中一种化合物ZSW与STAT3的SH2结构域结合，导致TNBC细胞中STAT3表达和激活降低。此外，ZSW促进STAT3泛素化，在体外抑制TNBC细胞增殖，并在体内以可控毒性减弱肿瘤生长。ZSW还通过抑制STAT3减少乳腺癌干细胞（BCSC）的乳腺球形成。
结论
我们得出结论，新型异恶唑并喹啉ZSW可能被开发为一种癌症治疗药物，因为它靶向STAT3，从而抑制癌细胞的干性。
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