title: Dual inhibition of survivin and MAOA synergistically impairs growth of PTEN-negative prostate cancer.
abstract: BACKGROUND
  Survivin and monoamine oxidase A (MAOA) levels are elevated in prostate cancer (PCa) compared to normal prostate glands. However, the relationship between survivin and MAOA in PCa is unclear.
  
  
  METHODS
  We examined MAOA expression in the prostate lobes of a conditional PTEN-deficient mouse model mirroring human PCa, with or without survivin knockout. We also silenced one gene at a time and examined the expression of the other. We further evaluated the combination of MAOA inhibitors and survivin suppressants on the growth, viability, migration and invasion of PCa cells.
  
  
  RESULTS
  Survivin and MAOA levels are both increased in clinical PCa tissues and significantly associated with patients' survival. Survivin depletion delayed MAOA increase during PCa progression, and silencing MAOA decreased survivin expression. The combination of MAOA inhibitors and the survivin suppressants (YM155 and SC144) showed significant synergy on the inhibition of PCa cell growth, migration and invasion with concomitant decrease in survivin and MMP-9 levels.
  
  
  CONCLUSIONS
  There is a positive feedback loop between survivin and MAOA expression in PCa. Considering that survivin suppressants and MAOA inhibitors are currently available in clinical trials and clinical use, their synergistic effects in PCa support a rapid translation of this combination to clinical practice.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, Translational Oncology Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: H
authors.initials: H
authors.lastname: Adisetiyo
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, Translational Oncology Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: S
authors.initials: S
authors.lastname: Tamura
authors.affiliation: Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, Arcavacata di Rende, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Grande
authors.affiliation: Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Università della Calabria, Arcavacata di Rende, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Garofalo
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: P
authors.initials: P
authors.lastname: Roy-Burman
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, Translational Oncology Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: N
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000032:analysis / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008995:Monoamine Oxidase / Q000032:analysis*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000032:analysis*; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D011810:Quinoxalines / Q000494:pharmacology; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D006834:Hydrazines; D051034:Inhibitor of Apoptosis Proteins; D008996:Monoamine Oxidase Inhibitors; C544427:N'-(7-fluoroH-pyrrolo(1,2-a)quinoxalin-4-yl)pyrazine-2-carbohydrazide; D011810:Quinoxalines; D000077022:Survivin; D008995:Monoamine Oxidase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human