PMID- 33905554
OWN - NLM
STAT- MEDLINE
DCOM- 20211228
LR  - 20211228
IS  - 1097-0045 (Electronic)
IS  - 0270-4137 (Linking)
VI  - 81
IP  - 9
DP  - 2021 Jun
TI  - Proteomic analysis of extracellular vesicles identified PI3K pathway as a 
      potential therapeutic target for cabazitaxel-resistant prostate cancer.
PG  - 592-602
LID - 10.1002/pros.24138 [doi]
AB  - BACKGROUND: Cabazitaxel (CBZ) is now widely used for prostate cancer (PC) 
      patients resistant to docetaxel (DOC), however, most patients eventually acquire 
      resistance. It will, therefore, be of great benefit to discover novel therapeutic 
      target for the resistance. We aimed to identify candidate therapeutic targets for 
      CBZ-resistance by proteomic analysis of extracellular vesicles (EVs) isolated 
      from serum of DOC-resistant PC patients who later developed CBZ-resistance as 
      well as those harvested from culture medium of DOC- and CBZ-resistant PC cell 
      lines. METHODS: Using T-cell immunoglobulin domain and mucin domain-containing 
      protein 4 (Tim4) conjugated to magnetic beads, EVs were purified from serum of PC 
      patients with DOC-resistance that was collected before and after acquiring 
      CBZ-resistance and conditioned medium of DOC-resistant (22Rv1DR) and 
      CBZ-resistant (22Rv1CR) PC cell lines. Protein analysis of EVs was performed by 
      nanoLC-MS/MS, followed by a comparative analysis of protein expression and 
      network analysis. The cytotoxic effect of a phosphatidylinositol-3-kinase (PI3K) 
      inhibitor, ZSTK474, was evaluated by WST-1 assay. The expression and 
      phosphorylation of PI3K and PTEN were examined by western blot analysis. RESULTS: 
      Among differentially regulated proteins, 77 and 61 proteins were significantly 
      increased in EVs from CBZ-resistant PC cell line and patients, respectively. A 
      comparison between the two datasets revealed that six proteins, 
      fructose-bisphosphate aldolase, cytosolic nonspecific dipeptidase, CD63, CD151, 
      myosin light chain 9, and peroxiredoxin-6 were elevated in EVs from both cell 
      line and patients. Network analysis of the increased EV proteins identified 
      pathways associated with CBZ-resistance including PI3K signaling pathway. ZSTK474 
      significantly inhibited growth of 22Rv1CR cells and improved their sensitivity to 
      CBZ. In 22Rv1CR cells, PI3K was activated and PTEN that inhibits PI3K was 
      deactivated. CONCLUSIONS: Proteomic analysis of serum EVs was successfully 
      accomplished by using Tim-4 as a tool to isolate highly purified EVs. Our results 
      suggest that the combination use of CBZ and PI3K inhibitor could be a promising 
      treatment option for CBZ-resistant PC patients.
CI  - (c) 2021 Wiley Periodicals LLC.
FAU - Hishida, Seiji
AU  - Hishida S
AD  - Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan.
FAU - Kawakami, Kyojiro
AU  - Kawakami K
AD  - Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of 
      Gerontology, Tokyo, Japan.
FAU - Fujita, Yasunori
AU  - Fujita Y
AD  - Research Team for Functional Biogerontology, Tokyo Metropolitan Institute of 
      Gerontology, Tokyo, Japan.
FAU - Kato, Taku
AU  - Kato T
AD  - Department of Urology, Asahi University Hospital, Gifu, Japan.
FAU - Takai, Manabu
AU  - Takai M
AD  - Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan.
FAU - Iinuma, Koji
AU  - Iinuma K
AD  - Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan.
FAU - Nakane, Keita
AU  - Nakane K
AD  - Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan.
FAU - Tsuchiya, Tomohiro
AU  - Tsuchiya T
AD  - Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan.
FAU - Koie, Takuya
AU  - Koie T
AD  - Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan.
FAU - Miura, Yuri
AU  - Miura Y
AD  - Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of 
      Gerontology, Tokyo, Japan.
FAU - Ito, Masafumi
AU  - Ito M
AD  - Research Team for Functional Biogerontology, Tokyo Metropolitan Institute of 
      Gerontology, Tokyo, Japan.
FAU - Mizutani, Kosuke
AU  - Mizutani K
AUID- ORCID: 0000-0001-5767-5314
AD  - Department of Urology, Gifu University Graduate School of Medicine, Gifu, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210427
PL  - United States
TA  - Prostate
JT  - The Prostate
JID - 8101368
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Taxoids)
RN  - 15H5577CQD (Docetaxel)
RN  - 51F690397J (cabazitaxel)
SB  - IM
MH  - Antineoplastic Agents/pharmacology
MH  - Cell Line, Tumor
MH  - Docetaxel/*pharmacology
MH  - Drug Discovery/methods
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Extracellular Vesicles/*metabolism
MH  - Humans
MH  - Male
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors/*pharmacology
MH  - *Prostatic Neoplasms/drug therapy/metabolism/pathology
MH  - Proteomics/methods
MH  - Signal Transduction/drug effects
MH  - Taxoids/*pharmacology
OTO - NOTNLM
OT  - cabazitaxel
OT  - docetaxel
OT  - extracellular vesicles
OT  - phosphatidylinositol-3-kinase
OT  - prostate cancer
OT  - proteomic analysis
EDAT- 2021/04/28 06:00
MHDA- 2021/12/29 06:00
CRDT- 2021/04/27 17:23
PHST- 2021/03/07 00:00 [revised]
PHST- 2020/12/10 00:00 [received]
PHST- 2021/04/11 00:00 [accepted]
PHST- 2021/04/28 06:00 [pubmed]
PHST- 2021/12/29 06:00 [medline]
PHST- 2021/04/27 17:23 [entrez]
AID - 10.1002/pros.24138 [doi]
PST - ppublish
SO  - Prostate. 2021 Jun;81(9):592-602. doi: 10.1002/pros.24138. Epub 2021 Apr 27.