title: Down-regulation of calcium/calmodulin-dependent protein kinase kinase 2 by androgen deprivation induces castration-resistant prostate cancer.
abstract: 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.
authors.affiliation: Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Mizokami
authors.forename: Toru
authors.initials: T
authors.lastname: Miyagi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawai
authors.forename: Kouji
authors.initials: K
authors.lastname: Izumi
authors.forename: Misako
authors.initials: M
authors.lastname: Kumaki
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Ofude
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
authors.forename: Mikio
authors.initials: M
authors.lastname: Namiki
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000473:pathology; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C517700:Camkk2 protein, mouse