title: CCR1/CCL5 interaction promotes invasion of taxane-resistant PC3 prostate cancer cells by increasing secretion of MMPs 2/9 and by activating ERK and Rac signaling.
abstract: Castration-refractory prostate cancer (CRPC) is treated with taxane-based chemotherapy, but eventually becomes drug resistant. It is thus essential to identify novel therapeutic targets for taxane resistance in CRPC patients. We investigated the role of the chemokine (C-C motif) receptor 1 (CCR1) and its ligand, chemokine (C-C motif) ligand 5 (CCL5), in taxane-resistant CRPC using paclitaxel-resistant prostate cancer cells (PC3PR) established from PC3 cells. We found that the expression levels of CCR1 mRNA and protein were up-regulated in PC3PR cells compared to PC3 cells. In order to investigate the role of increased CCR1 in PC3PR cells, we stimulated cells with CCL5, one of the chemokine ligands of CCR1. In CCL5-stimulated PC3PR cells, siRNA-mediated knockdown of CCR1 expression reduced phosphorylation of ERK1/2 and Rac1/cdc42. Furthermore, CCR1 knockdown and MEK1/2 inhibition decreased CCL5-stimulated secretion of MMPs 2 and 9, which play important roles in cancer cell invasion and metastasis. In the Matrigel invasion assay, knockdown of CCR1 and inhibition of the ERK and Rac signaling pathways significantly decreased the number of invading cells. Finally, the serum CCL5 protein level as measured by ELISA was not different among the three groups of patients: those with negative prostate biopsy, those at initial diagnosis of prostate cancer, and those with taxane-resistant prostate cancer. These results demonstrated for the first time that the interaction of CCR1 with CCL5 caused by increased expression of CCR1 promotes invasion of PC3PR cells by increasing secretion of MMPs 2 and 9 and by activating ERK and Rac signaling. Our findings suggest that CCR1 could be a novel therapeutic target for taxane-resistant CRPC.
authors.affiliation: Department of Urology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1193, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Kato
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fujita
authors.forename: Keita
authors.initials: K
authors.lastname: Nakane
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mizutani
authors.forename: Riyako
authors.initials: R
authors.lastname: Terazawa
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Ehara
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kanimoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Kojima
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nozawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Deguchi
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
mesh_terms: D000368:Aged; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018946:Chemokine CCL5 / Q000097:blood / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D054389:Receptors, CCR1 / Q000235:genetics / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D001952:Bridged-Ring Compounds; C483024:CCL5 protein, human; C515300:CCR1 protein, human; D018946:Chemokine CCL5; C107953:RAC1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054389:Receptors, CCR1; D043823:Taxoids; C080625:taxane; C482128:MAP2K2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein
keywords: CCL5; CCR1; Cancer cell invasion; MMP; Taxane-resistant prostate cancer