title: Metformin represses androgen-dependent and androgen-independent prostate cancers by targeting androgen receptor.
abstract: BACKGROUND
  Metformin has been reported to inhibit the growth of different types of cancers, including prostate cancer. We were interested to understand if the effect of metformin on prostate cancer is AR-dependent and, if so, whether metformin could act synergistically with the other anti-AR agents to serve as a therapeutic regimen with high efficacy and low toxicity.
  
  
  METHODS
  Cell viabilities and apoptosis were determined by MTT assay and annexin V-FITC staining, respectively, when the two human prostate cancer cell lines, the androgen-dependent LNCaP and the androgen-independent 22RV1 were treated with metformin alone or in combination with bicalutamide. Quantitative RT-PCR and western blotting assays were conducted to examine metformin effects on AR mRNA and protein levels, respectively. Chromatin immunoprecipitation (ChIP) assays were conducted to confirm the recruitment of AR to the ARE(s) located on the promoter region of the AR target gene PSA.
  
  
  RESULTS
  Metformin treatment reduced cell viability and enhanced apoptosis for both cell lines and additive effects were observed when LNCaP cells were treated with combined metformin and bicalutamide. Metformin down-regulated full-length AR protein in LNCaP cells. Both full-length and the truncated AR (AR-v7) were down-regulated by metformin in CWR22Rv1 cells. In both LNCaP and CWR22Rv1 cells, metformin repressed AR signaling pathway not by affecting AR protein degradation/stability, but rather through down-regulating the levels of AR mRNAs.
  
  
  CONCLUSIONS
  Metformin represses prostate cancer cell viability and enhances apoptosis by targeting the AR signaling pathway. Combinations of metformin and other anti-AR agents pose a potentially promising therapeutic approach for treatment of prostate cancers, especially the castrate-resistant prostate cancer, with high efficacy and low toxicity.
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: Gaolei
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: Dali
authors.initials: D
authors.lastname: Tong
authors.affiliation: Department of Bio-Medical Sciences, Philadelphia College of osteopathic Medicine, Philadelphia, Pennsylvania.
authors.forename: Henna
authors.initials: H
authors.lastname: Parmar
authors.affiliation: Department of Bio-Medical Sciences, Philadelphia College of osteopathic Medicine, Philadelphia, Pennsylvania.
authors.forename: Donald
authors.initials: D
authors.lastname: Hasenmayer
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Bio-Medical Sciences, Philadelphia College of osteopathic Medicine, Philadelphia, Pennsylvania.
authors.forename: Dianzheng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Jiang
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism*; D000813:Anilides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014105:Tosyl Compounds / Q000494:pharmacology*
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D009570:Nitriles; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D008687:Metformin; C053541:bicalutamide; D017430:Prostate-Specific Antigen
keywords: androgen receptor; castration resistance; metformin; prostate cancer