title: Pharmacological methyl group donors block skeletal metastasis in vitro and in vivo.
abstract: OBJECTIVE
  DNA hypomethylation was previously implicated in metastasis. In the present study, we examined whether methyl supplementation with the universal methyl donor S-adenosylmethionine (SAM) inhibits prostate cancer associated skeletal metastasis.
  
  
  METHODS
  Highly invasive human prostate cancer cells PC-3 and DU-145 were treated with vehicle alone, S-adenosylhomocysteine (SAH) or SAM and their effects on tumour cell proliferation, invasion, migration and colony formation were monitored. For in vivo studies, control (SAH) and SAM-treated PC-3 cells were injected into the tibia of Fox chase SCID mice and skeletal lesions were determined by X-ray and μCT. To understand possible mechanisms involved, we delineated the effect of SAM on the genome-wide methylation profile of PC-3 cells.
  
  
  RESULTS
  Treatment with SAM resulted in a dose-dependent inhibition of tumour cell proliferation, invasion, cell migration, colony formation and cell cycle characteristics. Animals injected with 250 μM SAM-treated cells developed significantly smaller skeletal lesions, which were associated with increases in bone volume to tumour volume ratio and connectivity density as well as decreased trabecular spacing. Genome-wide methylation analysis showed differential methylation in several key signalling pathways implicated in prostate cancer including the signal transducer and activator of transcription 3 (STAT3) pathway. A selective STAT3 inhibitor decreased tumour cell invasion, effects which were less pronounced as compared with SAM.
  
  
  CONCLUSIONS
  These studies provide a possible mechanism for the role of DNA demethylation in the development of skeletal metastasis and a rationale for the use of hypermethylation pharmacological agents to impede the development and progression of skeletal metastasis.
authors: Department of Medicine, McGill University Health Center, Montreal, QC, Canada.
authors: Nicholas
authors: N
authors: Shukeir
authors: Department of Pharmacology and Therapeutics, McGill University Health Center, Montreal, QC, Canada.|Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.
authors: Barbara
authors: B
authors: Stefanska
authors: Department of Medicine, McGill University Health Center, Montreal, QC, Canada.
authors: Surabhi
authors: S
authors: Parashar
authors: Department of Pharmacology and Therapeutics, McGill University Health Center, Montreal, QC, Canada.
authors: Flora
authors: F
authors: Chik
authors: Department of Medicine, McGill University Health Center, Montreal, QC, Canada.
authors: Ani
authors: A
authors: Arakelian
authors: Department of Pharmacology and Therapeutics, McGill University Health Center, Montreal, QC, Canada.
authors: Moshe
authors: M
authors: Szyf
authors: Department of Medicine, McGill University Health Center, Montreal, QC, Canada.
authors: Shafaat A
authors: SA
authors: Rabbani
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000556:secondary; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects; D055114:X-Ray Microtomography
chemical_list: D012436:S-Adenosylmethionine
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