Although docetaxel (DOX) is the standard of care for advanced prostate cancer (PCa), most patients develop resistance to DOX. Therefore, elucidating the mechanism that underlies resistance to DOX is critical to enhance therapeutic intervention. Mining cDNA microarray from the PC-3 PCa cell line and its DOX-resistant derivative (PC3-TxR) revealed decreased latexin (LXN) expression in the resistant cells. LXN expression was inversely correlated with taxane resistance in a panel of PCa cell lines. LXN knockdown conferred DOX resistance to PCa cells in vitro and in vivo; whereas LXN overexpression reduced DOX resistance in several PCa cell lines. A mouse model of PCa demonstrated that PCa cells developed resistance to DOX in the bone microenvironment, but not the soft tissue microenvironment. This was associated with decreased LXN expression in PCa cells in the bone microenvironment compared to the soft tissue microenvironment. It was identified that bone stromal cells decreased LXN expression through methylation and induced chemoresistance in PCa in vitro. These findings reveal that a subset of PCa develops DOX resistance through loss of LXN expression associated with methylation and that the bone microenvironment promotes this drug resistance phenotype.
This study suggests that the latexin pathway should be further explored as a viable target for preventing or reversing taxane resistance in PCa.
Molecular cancer research : MCR. 2017 Jan 13 [Epub ahead of print]
Mi Zhang, Mary Osisami, Jinlu Dai, Jill M Keller, June Escara-Wilke, Atsushi Mizokami, Evan T Keller
Clinical Medicine Program, Central South University, Xiangya Hospital., Urology, University of Michigan., Unit for Laboratory Animal Medicine, University of Michigan., Urology, Kanazawa University., Biointerfaces Institute, University of Michigan .