PMID- 22549914
OWN - NLM
STAT- MEDLINE
DCOM- 20130116
LR  - 20131121
IS  - 1097-0045 (Electronic)
IS  - 0270-4137 (Linking)
VI  - 72
IP  - 16
DP  - 2012 Dec 1
TI  - Down-regulation of calcium/calmodulin-dependent protein kinase kinase 2 by 
      androgen deprivation induces castration-resistant prostate cancer.
PG  - 1789-801
LID - 10.1002/pros.22533 [doi]
AB  - BACKGROUND: Conversion into androgen-hypersensitive state and adaptation to the 
      low concentration of androgen during ADT cause relapse of prostate cancer (PCa). 
      It is important to identify differentially expressed genes between PCa and normal 
      prostate tissues and to reveal the function of these genes that are involved in 
      progression of PCa. METHODS: We performed cDNA microarray analysis to identify 
      differentially expressed genes, calcium/calmodulin-dependent protein kinase 
      kinase 2 (CAMKK2). Immunohistochemical analysis was conducted to investigate the 
      relationship between the CAMKK2 expression level and prognosis. The function of 
      CAMKK2 was assessed by generating CAMKK2 overexpressed LNCaP cells and by 
      knockdown of CAMKK2. RESULTS: We identified CAMKK2 overexpressed six times in PCa 
      more than normal prostate by cDNA microarray analysis. Immunohistochemical 
      analysis of CAMKK2 protein showed that CAMKK2 protein was expressed more in PCa 
      than normal tissue. However, the expression in the high-grade PCa diminished. 
      Moreover, the narrowness of CAMKK2-positive area before ADT was a poor prognostic 
      factor. Androgen-deprivation treatment from the medium in which LNCaP cells were 
      cultured in the presence of 10 nM DHT repressed CAMKK2 expression. CAMKK2 
      overexpressed LNCaP cells (LNCaP/GFP-CAMKK2) attenuated androgen-sensitivity. 
      Tumorigenesis of LNCaP/GFP-CAMKK2 cells in male SCID mice was decreased compared 
      with control cells irrespective of castration. Finally, knockdown of CAMKK2 mRNA 
      in LNCaP cells induced androgen-hypersensitivity and stimulated LNCaP cell 
      proliferation. CONCLUSIONS: Induction of androgen-hypersensitivity after ADT may 
      be involved in down-regulation of CAMKK2. This result may provide new therapeutic 
      approach to keep androgen-sensitivity of PCa after ADT.
CI  - Copyright (c) 2012 Wiley Periodicals, Inc.
FAU - Shima, Takashi
AU  - Shima T
AD  - Department of Integrative Cancer Therapy and Urology, Kanazawa University 
      Graduate School of Medical Sciences, Ishikawa, Japan.
FAU - Mizokami, Atsushi
AU  - Mizokami A
FAU - Miyagi, Toru
AU  - Miyagi T
FAU - Kawai, Keiichi
AU  - Kawai K
FAU - Izumi, Kouji
AU  - Izumi K
FAU - Kumaki, Misako
AU  - Kumaki M
FAU - Ofude, Mitsuo
AU  - Ofude M
FAU - Zhang, Jian
AU  - Zhang J
FAU - Keller, Evan T
AU  - Keller ET
FAU - Namiki, Mikio
AU  - Namiki M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120501
PL  - United States
TA  - Prostate
JT  - The Prostate
JID - 8101368
RN  - 0 (Androgens)
RN  - 0 (Receptors, Androgen)
RN  - 08J2K08A3Y (Dihydrotestosterone)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase)
RN  - EC 2.7.11.17 (Camkk2 protein, mouse)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - Androgens/*deficiency/genetics/metabolism
MH  - Animals
MH  - Calcium-Calmodulin-Dependent Protein Kinase Kinase/*genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Transformation, Neoplastic/*drug effects/genetics/pathology
MH  - Dihydrotestosterone/pharmacology
MH  - Down-Regulation/*drug effects/genetics
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, SCID
MH  - Middle Aged
MH  - Orchiectomy
MH  - Prostatic Neoplasms/*genetics/metabolism/pathology
MH  - Receptors, Androgen/genetics/metabolism
EDAT- 2012/05/03 06:00
MHDA- 2013/01/17 06:00
CRDT- 2012/05/03 06:00
PHST- 2012/01/29 00:00 [received]
PHST- 2012/04/03 00:00 [accepted]
PHST- 2012/05/03 06:00 [entrez]
PHST- 2012/05/03 06:00 [pubmed]
PHST- 2013/01/17 06:00 [medline]
AID - 10.1002/pros.22533 [doi]
PST - ppublish
SO  - Prostate. 2012 Dec 1;72(16):1789-801. doi: 10.1002/pros.22533. Epub 2012 May 1.