title: Metformin effects on biochemical recurrence and metabolic signaling in the prostate.
abstract: BACKGROUND
  Metformin has received considerable attention as a potential anti-cancer agent. Animal and in-vitro prostate cancer (PCa) models have demonstrated decreased tumor growth with metformin, however the precise mechanisms are unknown. We examine the effects of metformin on PCa biochemical recurrence (BCR) in a large clinical database followed by evaluating metabolic signaling changes in a cohort of men undergoing prostate needle biopsy (PNB).
  
  
  METHODS
  Men treated for localized PCa were identified in a comprehensive clinical database between 2001 and 2010. Cox regression was performed to determine association with BCR relative to metformin use. We next identified a separate case-control cohort of men undergoing prostate needle biopsy (PNB) stratified by metformin use. Differences in mean IHC scores were compared with linear regression for phosphorylated IR, IGF-IR, AKT, and AMPK.
  
  
  RESULTS
  One thousand seven hundred and thirty four men were evaluated for BCR with mean follow up of 41 months (range 1-121 months). "Ever" metformin use was not associated with BCR (HR 1.12, 0.77-1.65), however men reporting both pre/post-treatment metformin use had a 45% reduction in BCR (HR = 0.55 (0.31-0.96)). For the tissue-based study, 48 metformin users and 42 controls underwent PNB. Significantly greater staining in phosphorylated nuclear (p-IR, p-AKT) and cytoplasmic (p-IR, p-IGF-1R) insulin signaling proteins were seen in patients with PCa detected compared to those with negative PNB (P-values all <0.006). When stratified by metformin use, IGF-1R remained significantly elevated (P = 0.01) in men with PCa detected whereas p-AMPK (P = 0.05) was elevated only in those without PCa.
  
  
  CONCLUSIONS
  Metformin use is associated with reduced BCR after treatment of localized PCa when considering pre-diagnostic and cumulative dosing. In men with cancer detected on PNB, insulin signaling markers were significantly elevated compared to negative PNB patients. The finding of IGF-1R elevation in positive PNBs versus p-AMPK elevation in negative PNBs suggests altered metabolic pathway activation precipitated by metformin use.
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Brian
authors.initials: B
authors.lastname: Winters
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, Washington.|Health Services Research & Development and GRECC, VA Puget Sound Health Care System, Seattle, Washington.
authors.forename: Stephen
authors.initials: S
authors.lastname: Plymate
authors.affiliation: Health Services Research & Development and GRECC, VA Puget Sound Health Care System, Seattle, Washington.|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Zeliadt
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Sarah
authors.initials: S
authors.lastname: Holt
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Xiaotun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Health Services Research & Development and GRECC, VA Puget Sound Health Care System, Seattle, Washington.
authors.forename: Elaine
authors.initials: E
authors.lastname: Hu
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington.|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lin
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Bryan
authors.initials: B
authors.lastname: Wooldridge
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: John L
authors.initials: JL
authors.lastname: Gore
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Porter
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington.|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Wright
mesh_terms: D000368:Aged; D016208:Databases, Factual; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D012306:Risk; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt
keywords: AMPK; insulin signaling; metformin; prostate cancer; veterans affairs