Antiproliferative effect of HSP90 inhibitor Y306zh against pancreatic cancer is mediated by interruption of AKT and MAPK signaling pathways.

Abstract

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