Current Cancer Drug Targets

Ruiwen Zhang 
Texas Tech University Health Sciences Center
1300 Coulter Drive
Amarillo, TX 79106
USA

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

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

Graphical Abstract:


Abstract:

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.

Keywords: Chaperone complexes, client protein, HSP90, pancreatic cancer, p23, Y306zh.

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Article Details

VOLUME: 14
ISSUE: 7
Year: 2014
Page: [671 - 683]
Pages: 13
DOI: 10.2174/1568009614666140908101523
Price: $58