HSP90抑制剂Y306zh对抗胰腺癌的抗增殖效应是通过中断AKT和MAPK信号通路介导的

Title:Antiproliferative Effect of HSP90 Inhibitor Y306zh Against Pancreatic Cancer is Mediated by Interruption of AKT and MAPK Signaling Pathways

Volume: 14 Issue: 7

Author(s): Nina Xue, Jing Jin, Di Liu, Rui Yan, Sen Zhang, Xiaoming Yu and Xiaoguang Chen

Affiliation:

关键词: 分子伴侣复合体，客户蛋白，热休克蛋白90，胰腺癌，p23

摘要: Background and Aim: Inhibition of HSP90 is a potential strategy to treat pancreatic cancer (PC), since many client proteins of HSP90 are found to be over-expressed and/or genetically mutated in PC. These client proteins directly participate in the modulation of proliferation and aggravation of PC. Our previous works led to Y306zh as a novel and potent HSP90 inhibitor. In this study we further investigated the mode of actions of Y306zh as an anti-PC agent.

Materials and Methods: The binding affinity of Y306zh towards HSP90 was analyzed by fluorescence polarization assay. The anti-proliferative activities and molecular mechanism of Y306zh were investigated in human PC cell lines and Miapaca2 xenograft model.

Results: Y306zh binds tightly to the NH₂-terminus of HSP90 with an IC₅₀ of 85 nM, and this causes ATP incapable to attach to the same binding site, and disrupts HSP90-p23 association. Y306zh also induces the expression of HSP70, recruits the complex of CHIP, HSP70 and HSP90, and eventually results in the degradation of HSP90 client proteins (EGFR, AKT, C-RAF and CDK4) via proteasomal pathway. Amazingly, coincident with the molecular mechanism, Y306zh also inhibits the proliferation of PC cells through G2/M phase arrest, but appears to be totally insensitive to normal mammalian cells. Furthermore, Y306zh effectively inhibits tumor growth of Mia-paca2 xenograft mice without any obvious effect on body weight.

Conclusions: Y306zh, a novel HSP90 inhibitor, interrupts ATP binding to HSP90 and disrupts HSP90-p23 interaction, and eventually inhibits the growth of PC cells.

Cite this article as:

Xue Nina, Jin Jing, Liu Di, Yan Rui, Zhang Sen, Yu Xiaoming and Chen Xiaoguang, Antiproliferative Effect of HSP90 Inhibitor Y306zh Against Pancreatic Cancer is Mediated by Interruption of AKT and MAPK Signaling Pathways, Current Cancer Drug Targets 2014; 14 (7) . https://dx.doi.org/10.2174/1568009614666140908101523