title: Residual prostate cancer cells after docetaxel therapy increase the tumorigenic potential via constitutive signaling of CXCR4, ERK1/2 and c-Myc.
abstract: Despite an increasing prevalence of patients with docetaxel-refractory prostate cancer, little is known about the tumor biology of the docetaxel-resistant residual tumor cells compared with primary tumor cells. In this study, tumorigenic potential was increased in the docetaxel-resistant residual prostate cancer cell lines (DRD, 1G7 and PC3DR) compared with parental cells (DU145 or PC3). Enhanced tumorigenic potential was conferred by oncogenic c-Myc, which was stabilized by constitutively activated ERK1/2 in DRD, 1G7, and PC3DR cells. Constitutively activated ERK1/2 was maintained by CXCR4, which was upregulated in DRD, 1G7, and PC3DR cells. In docetaxel-treated DU145 cells, transiently activated ERK1/2 induced CXCR4 expression by stabilizing c-Myc. Furthermore, constitutive activation of CXCR4, ERK1/2, and c-Myc signaling was evident in clinical tissue samples from human patients with docetaxel-resistant prostate cancer. In DTX-resistant residual prostate cancer cells, the enhanced tumorigenic potential was reduced by ERK1/2 inhibition, or by AMD3100, a CXCR4 antagonist. Thus, docetaxel treatment constitutively activated the CXCR4, ERK1/2, and c-Myc signaling loop in docetaxel-resistant residual prostate cancer cells.
  
  
  CONCLUSIONS
  Constitutive signaling pathways are viable therapeutic targets for residual prostate tumor cells following acquisition of docetaxel resistance.
authors.affiliation: Department of Urology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan. nono@uro.med.osaka-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Hatano
authors.forename: Souhei
authors.initials: S
authors.lastname: Yamaguchi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nimura
authors.forename: Kouki
authors.initials: K
authors.lastname: Murakami
authors.forename: Akira
authors.initials: A
authors.lastname: Nagahara
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Fujita
authors.forename: Motohide
authors.initials: M
authors.lastname: Uemura
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Nakai
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Masashi
authors.initials: M
authors.lastname: Nakayama
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001596:Benzylamines; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D000080027:Cyclams; D004195:Disease Models, Animal; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008819:Mice, Nude; D016513:Mice, SCID; D018365:Neoplasm, Residual / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D043823:Taxoids / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D019718:Receptors, CXCR4; D043823:Taxoids; D000077143:Docetaxel; C088327:plerixafor