PMID- 24662833
OWN - NLM
STAT- MEDLINE
DCOM- 20141105
LR  - 20220331
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 33
IP  - 36
DP  - 2014 Sep 4
TI  - Targeting autophagy overcomes Enzalutamide resistance in castration-resistant 
      prostate cancer cells and improves therapeutic response in a xenograft model.
PG  - 4521-30
LID - 10.1038/onc.2014.25 [doi]
AB  - Macro-autophagy is associated with drug resistance in various cancers and can 
      function as an adaptive response to maintain cell survival under metabolic 
      stresses, including androgen deprivation. Androgen deprivation or treatment with 
      androgen receptor (AR) signaling inhibitor (ARSI), Enzalutamide (MDV-3100, ENZA) 
      or bicalutamide induced autophagy in androgen-dependent and in 
      castration-resistant CaP (castration-resistant prostate cancer (CRPC)) cell 
      lines. The autophagic cascade triggered by AR blockage, correlated with the 
      increased light chain 3-II/I ratio and ATG-5 expression. Autophagy was observed 
      in a subpopulation of C4-2B cells that developed insensitivity to ENZA after 
      sustained exposure in culture. Using flow cytometry and clonogenic assays, we 
      showed that inhibiting autophagy with clomipramine (CMI), chloroquine or 
      metformin increased apoptosis and significantly impaired cell viability. This 
      autophagic process was mediated by AMP-dependent protein kinase (AMPK) activation 
      and the suppression of mammalian target of rapamycin (mTOR) through Raptor 
      phosphorylation (Serine 792). Furthermore, small interfering RNA targeting AMPK 
      significantly inhibited autophagy and promoted cell death in CaP cells acutely or 
      chronically exposed to ENZA or androgen deprivation, suggesting that autophagy is 
      an important survival mechanism in CRPC. Lastly, in vivo studies with mice 
      orthotopically implanted with ENZA-resistant cells demonstrated that the 
      combination of ENZA and autophagy modulators, CMI or metformin significantly 
      reduced tumor growth when compared with control groups (P<0.005). In conclusion, 
      autophagy is as an important mechanism of resistance to ARSI in CRPC. 
      Antiandrogen-induced autophagy is mediated through the activation of AMPK pathway 
      and the suppression of mTOR pathway. Blocking autophagy pharmacologically or 
      genetically significantly impairs prostate cancer cell survival in vitro and in 
      vivo, implying the therapeutics potential of autophagy inhibitors in the 
      antiandrogen-resistance setting.
FAU - Nguyen, H G
AU  - Nguyen HG
AD  - Department of Urology, UC Davis School of Medicine, Sacramento, CA, USA.
FAU - Yang, J C
AU  - Yang JC
AD  - Department of Urology, UC Davis School of Medicine, Sacramento, CA, USA.
FAU - Kung, H-J
AU  - Kung HJ
AD  - 1] Department of Biochemistry and Molecular Medicine, UC Davis School of 
      Medicine, Sacramento, CA, USA [2] UC Davis Comprehensive Cancer Center, UC Davis 
      School of Medicine, Sacramento, CA, USA.
FAU - Shi, X-B
AU  - Shi XB
AD  - Department of Urology, UC Davis School of Medicine, Sacramento, CA, USA.
FAU - Tilki, D
AU  - Tilki D
AD  - Department of Urology, UC Davis School of Medicine, Sacramento, CA, USA.
FAU - Lara, P N Jr
AU  - Lara PN Jr
AD  - UC Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, 
      CA, USA.
FAU - DeVere White, R W
AU  - DeVere White RW
AD  - 1] Department of Urology, UC Davis School of Medicine, Sacramento, CA, USA [2] UC 
      Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, CA, 
      USA.
FAU - Gao, A C
AU  - Gao AC
AD  - 1] Department of Urology, UC Davis School of Medicine, Sacramento, CA, USA [2] UC 
      Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, CA, 
      USA.
FAU - Evans, C P
AU  - Evans CP
AD  - 1] Department of Urology, UC Davis School of Medicine, Sacramento, CA, USA [2] UC 
      Davis Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, CA, 
      USA.
LA  - eng
GR  - P30 CA093373/CA/NCI NIH HHS/United States
GR  - R01 CA165263/CA/NCI NIH HHS/United States
GR  - R01 CA 165263/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20140324
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Androgen Receptor Antagonists)
RN  - 0 (Benzamides)
RN  - 0 (Nitriles)
RN  - 2010-15-3 (Phenylthiohydantoin)
RN  - 886U3H6UFF (Chloroquine)
RN  - 9100L32L2N (Metformin)
RN  - 93T0T9GKNU (enzalutamide)
RN  - NUV44L116D (Clomipramine)
SB  - IM
MH  - Androgen Receptor Antagonists/*therapeutic use
MH  - Animals
MH  - Autophagy/*drug effects
MH  - Benzamides
MH  - Cell Line, Tumor
MH  - Chloroquine/*pharmacology
MH  - Clomipramine/*pharmacology
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Male
MH  - Metformin/*pharmacology
MH  - Mice
MH  - Mice, SCID
MH  - Nitriles
MH  - Phenylthiohydantoin/*analogs & derivatives/therapeutic use
MH  - Prostatic Neoplasms, Castration-Resistant/drug therapy/pathology
MH  - Signal Transduction/drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC4155805
EDAT- 2014/03/26 06:00
MHDA- 2014/11/06 06:00
CRDT- 2014/03/26 06:00
PHST- 2013/10/17 00:00 [received]
PHST- 2013/12/05 00:00 [revised]
PHST- 2013/12/13 00:00 [accepted]
PHST- 2014/03/26 06:00 [entrez]
PHST- 2014/03/26 06:00 [pubmed]
PHST- 2014/11/06 06:00 [medline]
AID - onc201425 [pii]
AID - 10.1038/onc.2014.25 [doi]
PST - ppublish
SO  - Oncogene. 2014 Sep 4;33(36):4521-30. doi: 10.1038/onc.2014.25. Epub 2014 Mar 24.