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.

Attenuation of genome-wide 5-methylcytosine level is an epigenetic feature of cutaneous malignant melanomas

“…Consistent with reports in the literature [21,54], we observed a dose-dependent increase in DNA methylation by immunofluorescence, methylation-specific endonuclease digestion, and colorimetric ELISA assay. Furthermore, decreased proliferation of melanoma cells was associated with a significant reduction in proliferation in all five cell lines examined at 72 h. These results support our novel hypothesis that DNA hypomethylation is intrinsically required for melanoma survival.…”

“…Furthermore, decreased proliferation of melanoma cells was associated with a significant reduction in proliferation in all five cell lines examined at 72 h. These results support our novel hypothesis that DNA hypomethylation is intrinsically required for melanoma survival. Our findings are consistent with studies in osteosarcoma cell lines, where SAM treatment blocked cell proliferation and invasion in vitro and tumor metastasis in vivo [54]. Additional previous studies show that SAM is cytotoxic to carcinoma cells because in-vitro culture with SAM inhibited the growth of human gastric and colon cancer cells [21].…”

S‐Adenosylmethionine‐mediated apoptosis is potentiated by autophagy inhibition induced by chloroquine in human breast cancer cells

“…In fact, AdoMet is able to reverse the DNA hypomethylation status of both c‐Myc and H‐ras promoters, thus down regulating their expression in human gastric and colon cancer (Luo et al, ). Despite in recent years growing evidence has accumulated in the literature on the anti‐proliferative, anti‐metastatic, and proapoptotic effects of AdoMet in cancer cells (Ilisso et al, ; Li et al, ; Lu & Mato, , ; Martínez‐López et al, ; Pakneshan et al, ; Parashar et al, ; Shukeir et al, ), a clear understanding of the complex biological mechanisms exerted by AdoMet as well as their possible clinical applications are far to be defined.…”

“…It has been demonstrated that AdoMet treatment leads to a dose‐dependent decrease of proliferation and tumor invasion in human LM‐7 and MG‐63 osteosarcoma cells. At the molecular level, AdoMet treatment of osteosarcoma cells inhibits the expression of genes involved in metastatic processes, angiogenesis, and cell invasion (Parashar et al, ).…”

Effects of S‑adenosyl‑L‑methionine on the invasion and migration of head and neck squamous cancer cells and analysis of the underlying mechanisms

“…Another study demonstrated that in the highly invasive SW-620 colorectal cancer cell line, treatment with the sulfonium compound induced the inhibition of MMP2, and a decrease in membrane type 1 matrix metalloproteinase mRNA levels together with the upregulation of the tissue inhibitor of MMP2 (19). It was recently demonstrated that in human LM-7 and MG-63 osteosarcoma cells, AdoMet treatment led to a dose-dependent decrease in the proliferation and invasiveness of the tumor cells by inhibiting the expression of genes involved in the formation of metastasis, angiogenesis and cellular invasion, including uPA, MMP2 and MMP9 (20). More recently, it was reported that AdoMet was able to enhance the anti-metastatic effect of gemcitabine in pancreatic cancer through the inhibition of the JAK2/STAT3 pathway (21).…”