title: CSL regulates AKT to mediate androgen independence in prostate cancer progression.
abstract: BACKGROUND
  Aberrant signaling pathways leads to cancer initiation and progression. Both Notch and PI3K/AKT signaling pathways are believed to be involved in prostate cancer. How the interaction between the two pathways contributes to prostate cancer progression to androgen independence is still elusive.
  
  
  METHODS
  Prostate cancer cells were grown in RPMI 1,640 supplemented with 10% heat-inactivated fetal bovine serum (FBS) or 10% charcoal-stripped heat-inactivated fetal bovine serum (FCS), 1% penicillin-streptomycin in 75 cm2 polystyrene flasks, and maintained at 37 °C in a humidified atmosphere with 5% CO2 . Cell proliferation, invasion were performed with cell counting, matrigel assay in vitro. Dual luciferase assays were performed using reporter plasmids with ARE (Androgen Response Element, ARE). RNA interference was applied to gene silence. Tumorigenicity of cancer cells was evaluated by mouse xenograft in vivo.
  
  
  RESULTS
  A subpopulation of casodex resistant prostate cancer cells were identified with an overexpressed androgen receptor (AR) and aggressive phenotypes, characterized with high proliferation, invasion in vitro and enhanced tumorigenesis in vivo. Gene profiling for androgen-dependent LNCaP and androgen-independent LNCaP-CR revealed that both CSL and AKT gave the similar expressional pattern upon casodex treatment. Immunoblot demonstrated that CSL and AKT were dramatically suppressed in androgen dependent LNCaP cells, but slightly inhibited in LNCaP-CR cells as well as other androgen independent prostate cancer cells. Further studies indicated that CSL regulates AKT, and subsequently AR in prostate cancer cells. AKT mediates casodex resistance and androgen independence through regulation of cyclin D1.
  
  
  CONCLUSIONS
  CSL-AKT-AR axis might play an important role in prostate cancer progression. Targeting CSL depleted the casodex resistant population through inhibition of the AKT, suggesting a more effective therapeutic strategy for abrogating casodex resistance in advanced prostate cancer.
authors.affiliation: Jilin Medical University, Ji Lin, China.
authors.forename: Huiyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Landscape, Jiangxi Agricultural University, Nanchang, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jilin Agricultural University, Chang Chun, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Jilin Medical University, Ji Lin, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.affiliation: Jilin Medical University, Ji Lin, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Jilin Medical University, Ji Lin, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Jilin Medical University, Ji Lin, China.
authors.forename: Wenhe
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000502:physiology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011944:Receptors, Androgen / Q000502:physiology*; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000813:Anilides; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009570:Nitriles; C497570:RBPJ protein, human; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT signaling; CSL; casodex resistance; prostate cancer