Serum exosomal P-glycoprotein is a potential marker to diagnose docetaxel resistance and select a taxoid for patients with prostate cancer

Taku Kato, Kosuke Mizutani, Koji Kameyama, Kyojiro Kawakami, Yasunori Fujita, Keita Nakane, Yusuke Kanimoto, Hidetoshi Ehara, Hiroyasu Ito, Mitsuru Seishima, Takashi Deguchi, Masafumi Ito

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

Abstract

Objectives: 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 and materials: 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.

Original languageEnglish
Pages (from-to)385.e15-385.e20
JournalUrologic Oncology: Seminars and Original Investigations
Volume33
Issue number9
DOIs
Publication statusPublished - 01-09-2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Urology

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