SU4312通过抑制YAP和诱导对替莫唑胺作用的敏感性来抑制胶质瘤进展。
SU4312 Represses Glioma Progression by Inhibiting YAP and Inducing Sensitization to the Effect of Temozolomide.
作者信息
Wang Xu, Zhou Yi, Wang Yan, Wang Xiang, Zhang Yu, Mao Yufei, Zhang Long, Qi Ji, Zhang Yining, Lyu Feng, Gu Linbo, Yu Rutong, Zhou Xiuping
机构信息
Institute of Nervous System Diseases, Xuzhou Medical University, 84 West Huaihai Road, Xuzhou 221002, China.
Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou 221002, China.
出版信息
J Clin Med. 2022 Aug 16;11(16):4765. doi: 10.3390/jcm11164765.
SU4312, initially designed as a multi-target tyrosine kinase inhibitor, is consequently reported to inhibit tumor angiogenesis by blocking VEGFR. However, although SU4312 can penetrate the brain-blood barrier, its potential to inhibit glioma growth is unknown. In this study, we report that SU4312 inhibited glioma cell proliferation and down-regulated yes-associated protein (YAP), the key effector of the hippo pathway. The exogenous over-expression of YAP partially restored the inhibitory effect of SU4312 on glioma progression. Interestingly, SU4312 sensitized the antitumor effect of temozolomide, both in vitro and in vivo. Moreover, SU4312 decreased the M2tumor-associated macrophages and enhanced anti-tumor immunity by down-regulating the YAP-CCL2 axis. In conclusion, our results suggest that SU4312 represses glioma progression by down-regulating YAP transcription and consequently CCL2 secretion. SU4312 may be synergistic with temozolomide for glioma treatment.
SU4312最初被设计为一种多靶点酪氨酸激酶抑制剂，随后有报道称它可通过阻断血管内皮生长因子受体（VEGFR）来抑制肿瘤血管生成。然而，尽管SU4312能够穿透血脑屏障，但其抑制胶质瘤生长的潜力尚不清楚。在本研究中，我们报告SU4312抑制胶质瘤细胞增殖并下调Yes相关蛋白（YAP），即河马通路的关键效应因子。YAP的外源性过表达部分恢复了SU4312对胶质瘤进展的抑制作用。有趣的是，SU4312在体外和体内均增强了替莫唑胺的抗肿瘤作用。此外，SU4312通过下调YAP-CCL2轴减少了M2肿瘤相关巨噬细胞并增强了抗肿瘤免疫。总之，我们的结果表明SU4312通过下调YAP转录并因此减少CCL2分泌来抑制胶质瘤进展。SU4312可能与替莫唑胺协同用于胶质瘤治疗。
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