PMID- 27821815
OWN - NLM
STAT- MEDLINE
DCOM- 20180223
LR  - 20220317
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 7
IP  - 49
DP  - 2016 Dec 6
TI  - Everolimus (RAD001) sensitizes prostate cancer cells to docetaxel by 
      down-regulation of HIF-1alpha and sphingosine kinase 1.
PG  - 80943-80956
LID - 10.18632/oncotarget.13115 [doi]
AB  - Resistance to docetaxel is a key problem in current prostate cancer management. 
      Sphingosine kinase 1 (SK1) and phosphoinositide 3-kinase (PI3K)/Akt/mammalian 
      target of rapamycin (mTOR) pathways have been implicated in prostate cancer 
      chemoresistance. Here we investigated whether their combined targeting may 
      re-sensitize prostate cancer cells to docetaxel.In hormone-insensitive PC-3 and 
      DU145 prostate cancer cells the mTOR inhibitor everolimus (RAD001) alone did not 
      lead to significant cell death, however, it strongly sensitized cells to low 
      levels (5 nM) of docetaxel. We show that mTOR inhibition has led to a decrease in 
      hypoxia-inducible factor-1alpha (HIF-1alpha) protein levels and SK1 mRNA. HIF-1alpha 
      accumulation induced by CoCl2 has led to a partial chemoresistance to 
      RAD001/docetaxel combination. SK1 overexpression has completely protected 
      prostate cancer cells from RAD001/docetaxel effects. Using gene knockdown and 
      CoCl2 treatment we showed that SK1 mRNA expression is downstream of HIF-1alpha. In a 
      human xenograft model in nude mice single RAD001 and docetaxel therapies induced 
      23% and 15% reduction in prostate tumor volume, respectively, while their 
      combination led to a 58% reduction. RAD001 alone or in combination with docetaxel 
      has suppressed intratumoral mTOR and SK1 signaling, however as evidenced by tumor 
      size, it required docetaxel for clinical efficacy. Combination therapy was well 
      tolerated and had similar levels of toxicity to docetaxel alone.Overall, our data 
      demonstrate a new mechanism of docetaxel sensitization in prostate cancer. This 
      provides a mechanistic basis for further clinical application of RAD001/docetaxel 
      combination in prostate cancer therapy.
FAU - Alshaker, Heba
AU  - Alshaker H
AD  - School of Medicine, University of East Anglia, Norwich, UK.
AD  - Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and 
      Medical Sciences, University of Petra, Amman, Jordan.
FAU - Wang, Qi
AU  - Wang Q
AD  - School of Medicine, University of East Anglia, Norwich, UK.
FAU - Kawano, Yoshiaki
AU  - Kawano Y
AD  - Department of Urology, University of Kumamoto, Kumamoto, Japan.
FAU - Arafat, Tawfiq
AU  - Arafat T
AD  - Department of Pharmaceutical Medicinal Chemistry and Pharmacognosy, Faculty of 
      Pharmacy and Medical Sciences, University of Petra, Amman, Jordan.
FAU - Bohler, Torsten
AU  - Bohler T
AD  - Department of Surgery and Cancer, Imperial College London, London, UK.
FAU - Winkler, Mathias
AU  - Winkler M
AD  - Department of Surgery and Cancer, Imperial College London, London, UK.
FAU - Cooper, Colin
AU  - Cooper C
AD  - School of Medicine, University of East Anglia, Norwich, UK.
FAU - Pchejetski, Dmitri
AU  - Pchejetski D
AD  - School of Medicine, University of East Anglia, Norwich, UK.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Taxoids)
RN  - 15H5577CQD (Docetaxel)
RN  - 3G0H8C9362 (Cobalt)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EVS87XF13W (cobaltous chloride)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Cobalt/pharmacology
MH  - Docetaxel
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Drug Synergism
MH  - Everolimus/*pharmacology
MH  - Gene Expression Regulation, Enzymologic
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Male
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Phosphotransferases (Alcohol Group Acceptor)/genetics/*metabolism
MH  - Prostatic Neoplasms/*drug therapy/enzymology/genetics/pathology
MH  - RNA Interference
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - Taxoids/*pharmacology
MH  - Time Factors
MH  - Transfection
MH  - Tumor Burden/drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC5348367
OTO - NOTNLM
OT  - chemosensitization
OT  - docetaxel
OT  - everolimus (RAD001)
OT  - mTOR
OT  - prostate cancer
COIS- CONFLICTS OF INTEREST The authors declare that they have no conflicts of 
      interest.
EDAT- 2016/11/09 06:00
MHDA- 2018/02/24 06:00
PMCR- 2016/12/06
CRDT- 2016/11/09 06:00
PHST- 2016/10/07 00:00 [received]
PHST- 2016/10/27 00:00 [accepted]
PHST- 2016/11/09 06:00 [pubmed]
PHST- 2018/02/24 06:00 [medline]
PHST- 2016/11/09 06:00 [entrez]
PHST- 2016/12/06 00:00 [pmc-release]
AID - 13115 [pii]
AID - 10.18632/oncotarget.13115 [doi]
PST - ppublish
SO  - Oncotarget. 2016 Dec 6;7(49):80943-80956. doi: 10.18632/oncotarget.13115.