title: Serum exosomal P-glycoprotein is a potential marker to diagnose docetaxel resistance and select a taxoid for patients with prostate cancer.
abstract: OBJECTIVE
  Docetaxel is used as the first-line chemotherapy for castration-resistant prostate cancer (CRPC), but docetaxel resistance occurs in part owing to induction of P-glycoprotein (P-gp) encoded by multidrug resistance protein 1 (MDR1) gene. A recently developed taxane-cabazitaxel-has poor affinity for P-gp and is thereby effective in docetaxel-resistant CRPC. It has been recently demonstrated that exosomes in the body fluids could serve as a diagnostic marker because they contain proteins and RNAs specific to the cells from which they are derived. In this study, we aimed to investigate if P-gp in blood exosomes could be a marker to diagnose docetaxel resistance and select a taxoid for patients with CRPC.
  
  
  METHODS
  Exosomes were isolated by differential centrifugation from docetaxel-resistant prostate cancer (PC-3) cells (PC-3R) and their parental PC-3 cells and from the serum of patients. Silencing of P-gp was performed by small interfering RNA transfection. Protein expression was examined by Western blot analysis. Viability of cells treated with docetaxel or cabazitaxel was determined by water soluble tetrazolium salt (WST) assay.
  
  
  RESULTS
  The level of P-gp was higher in exosomes as well as cell lysates from PC-3R cells than in those from PC-3 cells. Cabazitaxel effectively killed PC-3R cells, and MDR1 knockdown improved the sensitivity of PC-3R cells to docetaxel but not to cabazitaxel. The P-gp level in blood exosomes was relatively higher in clinically docetaxel-resistant patients than in therapy-naïve patients.
  
  
  CONCLUSIONS
  Our results suggest that detection of P-gp in blood exosomes, which is involved in resistance to docetaxel but not to cabazitaxel, could be useful to diagnose docetaxel resistance and select an appropriate taxoid for patients with CRPC-docetaxel or cabazitaxel.
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan; Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Mizutani
authors.affiliation: Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kameyama
authors.affiliation: Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan.
authors.forename: Kyojiro
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Urology, Chutoen General Medical Center, Kakegawa, Shizuoka, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Nakane
authors.affiliation: Department of Urology, Chutoen General Medical Center, Kakegawa, Shizuoka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kanimoto
authors.affiliation: Department of Urology, Murakami Memorial Hospital, Asahi University, 3-23 Hashimoto-cho, Gifu, Gifu, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Ehara
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
authors.affiliation: Department of Urology, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Deguchi
authors.affiliation: Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan. Electronic address: mito@tmig.or.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D055354:Exosomes / Q000378:metabolism; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood*; D034741:RNA, Small Interfering; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D043823:Taxoids; D000077143:Docetaxel; C552428:cabazitaxel
keywords: Cabazitaxel; Castration-resistant prostate cancer; Docetaxel; Exosomes; Multidrug resistance protein 1/MDR1; P-glycoprotein/P-gp