PMID- 28615679
OWN - NLM
STAT- MEDLINE
DCOM- 20190109
LR  - 20220409
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 7
IP  - 1
DP  - 2017 Jun 14
TI  - Combination of RAD001 (everolimus) and docetaxel reduces prostate and breast 
      cancer cell VEGF production and tumour vascularisation independently of 
      sphingosine-kinase-1.
PG  - 3493
LID - 10.1038/s41598-017-03728-3 [doi]
LID - 3493
AB  - Resistance to docetaxel is a key problem in current prostate and breast cancer 
      management. We have recently discovered a new molecular mechanism of prostate 
      cancer docetaxel chemoresistance mediated by the mammalian target of rapamycin 
      (mTOR)/sphingosine-kinase-1 (SK1) pathway. Here we investigated the influence of 
      this pathway on vascular endothelial growth factor (VEGF) production and tumour 
      vascularisation in hormone resistant prostate and breast cancer models. 
      Immunofluorescent staining of tumour sections from human oestrogen receptor 
      (ER)-negative breast cancer patients showed a strong correlation between 
      phosphorylated P70S6 kinase (mTOR downstream target), VEGF and SK1 protein 
      expression. In hormone-insensitive prostate (PC3) and breast (MDA-MB-231 and 
      BT-549) cancer cell lines the mTOR inhibitor RAD001 (everolimus) has 
      significantly inhibited SK1 and VEGF expression, while low dose (5 nM) docetaxel 
      had no significant effect. In these cell lines, SK1 overexpression slightly 
      increased the basal levels of VEGF, but did not block the inhibitory effect of 
      RAD001 on VEGF. In a human prostate xenograft model established in nude mice, 
      RAD001 alone or in combination with docetaxel has suppressed tumour growth, VEGF 
      expression and decreased tumour vasculature. Overall, our data demonstrate a new 
      mechanism of an independent regulation of SK1 and VEGF by mTOR in 
      hormone-insensitive prostate and breast cancers.
FAU - Alshaker, Heba
AU  - Alshaker H
AD  - School of Medicine, University of East Anglia, Norwich, UK. halshaker@uop.edu.jo.
AD  - Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan. 
      halshaker@uop.edu.jo.
FAU - Wang, Qi
AU  - Wang Q
AD  - School of Medicine, University of East Anglia, Norwich, UK.
FAU - Bohler, Torsten
AU  - Bohler T
AD  - Department of Surgery and Cancer, Imperial College London, London, UK.
FAU - Mills, Robert
AU  - Mills R
AD  - Norfolk & Norwich University Hospital NHS Foundation Trust, Norwich, UK.
FAU - Winkler, Mathias
AU  - Winkler M
AD  - Department of Surgery and Cancer, Imperial College London, London, UK.
FAU - Arafat, Tawfiq
AU  - Arafat T
AD  - Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan.
FAU - Kawano, Yoshiaki
AU  - Kawano Y
AD  - Department of Urology, University of Kumamoto, Kumamoto, Japan.
FAU - Pchejetski, Dmitri
AU  - Pchejetski D
AD  - School of Medicine, University of East Anglia, Norwich, UK. 
      d.pshezhetskiy@uea.ac.uk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170614
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Antineoplastic Agents)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 15H5577CQD (Docetaxel)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*administration & dosage
MH  - Breast Neoplasms/*drug therapy/metabolism
MH  - Docetaxel/*administration & dosage
MH  - Everolimus/*administration & dosage
MH  - Female
MH  - Humans
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - PC-3 Cells
MH  - Phosphorylation
MH  - Phosphotransferases (Alcohol Group Acceptor)/*metabolism
MH  - Prostatic Neoplasms/*drug therapy/metabolism
MH  - Vascular Endothelial Growth Factor A/*metabolism
PMC - PMC5471177
COIS- The authors declare that they have no competing interests.
EDAT- 2017/06/16 06:00
MHDA- 2019/01/10 06:00
PMCR- 2017/06/14
CRDT- 2017/06/16 06:00
PHST- 2017/01/10 00:00 [received]
PHST- 2017/05/03 00:00 [accepted]
PHST- 2017/06/16 06:00 [entrez]
PHST- 2017/06/16 06:00 [pubmed]
PHST- 2019/01/10 06:00 [medline]
PHST- 2017/06/14 00:00 [pmc-release]
AID - 10.1038/s41598-017-03728-3 [pii]
AID - 3728 [pii]
AID - 10.1038/s41598-017-03728-3 [doi]
PST - epublish
SO  - Sci Rep. 2017 Jun 14;7(1):3493. doi: 10.1038/s41598-017-03728-3.