title: Bone Microenvironment Changes in Latexin Expression Promote Chemoresistance.
abstract: Although docetaxel is the standard of care for advanced prostate cancer, most patients develop resistance to docetaxel. Therefore, elucidating the mechanism that underlies resistance to docetaxel is critical to enhance therapeutic intervention. Mining cDNA microarray from the PC-3 prostate cancer cell line and its docetaxel-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 prostate cancer cell lines. LXN knockdown conferred docetaxel resistance to prostate cancer cellsin vitroandin vivo, whereas LXN overexpression reduced docetaxel resistance in several prostate cancer cell lines. A mouse model of prostate cancer demonstrated that prostate cancer cells developed resistance to docetaxel in the bone microenvironment, but not the soft tissue microenvironment. This was associated with decreased LXN expression in prostate cancer cells in the bone microenvironment compared with the soft tissue microenvironment. It was identified that bone stromal cells decreased LXN expression through methylation and induced chemoresistance in prostate cancerin vitroThese findings reveal that a subset of prostate cancer develops docetaxel resistance through loss of LXN expression associated with methylation and that the bone microenvironment promotes this drug resistance phenotype.Implications:This study suggests that the LXN pathway should be further explored as a viable target for preventing or reversing taxane resistance in prostate cancer.Mol Cancer Res; 15(4); 457-66. ©2017 AACR.
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Clinical Medicine Program, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Mary
authors.initials: M
authors.lastname: Osisami
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jinlu
authors.initials: J
authors.lastname: Dai
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan.|Unit for Laboratory Animal Medicine, University of Michigan; Ann Arbor, Michigan.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Keller
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan.
authors.forename: June
authors.initials: J
authors.lastname: Escara-Wilke
authors.affiliation: Department of Urology, Kanazawa University, Kanazawa, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizokami
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan. etkeller@umich.edu.|Biointerfaces Institute, University of Michigan; Ann Arbor, Michigan.
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology* / Q000187:drug effects; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000077143:Docetaxel; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D017154:Stromal Cells; D043823:Taxoids / Q000008:administration & dosage* / Q000494:pharmacology; D059016:Tumor Microenvironment; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000077143:Docetaxel; D009419:Nerve Tissue Proteins; D043823:Taxoids; D025521:Tumor Suppressor Proteins; C000611527:LXN protein, human