title: S-adenosylmethionine blocks osteosarcoma cells proliferation and invasion in vitro and tumor metastasis in vivo: therapeutic and diagnostic clinical applications.
abstract: Osteosarcoma (OS) is an aggressive and highly metastatic form of primary bone cancer affecting young children and adults. Previous studies have shown that hypomethylation of critical genes is driving metastasis. Here, we examine whether hypermethylation treatment can block OS growth and pulmonary metastasis. Human OS cells LM-7 and MG-63 were treated with the ubiquitous methyl donor S-adenosylmethionine (SAM) or its inactive analog S-adenosylhomocystine (SAH) as control. Treatment with SAM resulted in a dose-dependent inhibition of tumor cell proliferation, invasion, cell migration, and cell cycle characteristics. Inoculation of cells treated with 150 μmol/L SAM for 6 days into tibia or via intravenous route into Fox Chase severe combined immune deficient (SCID) mice resulted in the development of significantly smaller skeletal lesions and a marked reduction in pulmonary metastasis as compared to control groups. Epigenome wide association studies (EWAS) showed differential methylation of several genes involved in OS progression and prominent signaling pathways implicated in bone formation, wound healing, and tumor progression in SAM-treated LM-7 cells. Real-time polymerase chain reaction (qPCR) analysis confirmed that SAM treatment blocked the expression of several prometastatic genes and additional genes identified by EWAS analysis. Immunohistochemical analysis of normal human bone and tissue array from OS patients showed significantly high levels of expression of one of the identified gene platelet-derived growth factor alpha (PDGFA). These studies provide a possible mechanism for the role of DNA demethylation in the development and metastasis of OS to provide a rationale for the use of hypermethylation therapy for OS patients and identify new targets for monitoring OS development and progression.
authors.affiliation: Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Surabhi
authors.initials: S
authors.lastname: Parashar
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Cheishvili
authors.affiliation: Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Ani
authors.initials: A
authors.lastname: Arakelian
authors.affiliation: Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Zahid
authors.initials: Z
authors.lastname: Hussain
authors.affiliation: Fatima Memorial Hospital System, Lahore, Pakistan.
authors.forename: Imrana
authors.initials: I
authors.lastname: Tanvir
authors.affiliation: Fatima Memorial Hospital System, Lahore, Pakistan.
authors.forename: Haseeb Ahmed
authors.initials: HA
authors.lastname: Khan
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Moshe
authors.initials: M
authors.lastname: Szyf
authors.affiliation: Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Shafaat A
authors.initials: SA
authors.lastname: Rabbani
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001706:Biopsy; D001859:Bone Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D057890:Epigenomics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D012436:S-Adenosylmethionine / Q000008:administration & dosage / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D012436:S-Adenosylmethionine
keywords: DNA methylation; gene expression; osteosarcoma; patients; signaling pathways; tumor progression