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Br J Pharmacol. 2015 Jun;172(11):2769-81. doi: 10.1111/bph.13102. Epub 2015 Mar 27.

Pharmacological methyl group donors block skeletal metastasis in vitro and in vivo.

Author information

1
Department of Medicine, McGill University Health Center, Montreal, QC, Canada.
2
Department of Pharmacology and Therapeutics, McGill University Health Center, Montreal, QC, Canada.
3
Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.

Abstract

BACKGROUND AND PURPOSE:

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.

EXPERIMENTAL APPROACH:

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.

KEY 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 AND IMPLICATIONS:

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.

PMID:
25631332
PMCID:
PMC4439874
DOI:
10.1111/bph.13102
[Indexed for MEDLINE]
Free PMC Article

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