S-Adenosylmethionine Treatment of Colorectal Cancer Cell Lines Alters DNA Methylation, DNA Repair and Tumor Progression-Related Gene Expression

Abstract

Global DNA hypomethylation is a characteristic feature of colorectal carcinoma (CRC). The tumor inhibitory effect of S-adenosylmethionine (SAM) methyl donor has been described in certain cancers including CRC. However, the molecular impact of SAM treatment on CRC cell lines with distinct genetic features has not been evaluated comprehensively. HT-29 and SW480 cells were treated with 0.5 and 1 mmol/L SAM for 48 h followed by cell proliferation measurements, whole-genome transcriptome and methylome analyses, DNA stability assessments and exome sequencing. SAM reduced cell number and increased senescence by causing S phase arrest, besides, multiple EMT-related genes (e.g., TGFB1) were downregulated in both cell lines. Alteration in the global DNA methylation level was not observed, but certain methylation changes in gene promoters were detected. SAM-induced γ-H2AX elevation could be associated with activated DNA repair pathway showing upregulated gene expression (e.g., HUS1). Remarkable genomic stability elevation, namely, decreased micronucleus number and comet tail length was observed only in SW480 after treatment. SAM has the potential to induce senescence, DNA repair, genome stability and to reduce CRC progression. However, the different therapeutic responses of HT-29 and SW480 to SAM emphasize the importance of the molecular characterization of CRC cases prior to methyl donor supplementation.

S-Adenosylmethionine Inhibits Cell Growth and Migration of Triple Negative Breast Cancer Cells through Upregulating MiRNA-34c and MiRNA-449a

“…In addition, at pharmacological doses AdoMet has an excellent tolerability record without side effects [ 16 , 17 ]. Notably, in the last decade many in vitro and in vivo studies have shown promising anti-cancer properties of AdoMet, and growing scientific interest is now focusing on identifying the biological mechanisms and signal transduction pathways related to the antitumoral activity of this physiological compound [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ].…”

Mutual Correlation between Non-Coding RNA and S-Adenosylmethionine in Human Cancer: Roles and Therapeutic Opportunities

“…The antitumor effect of AdoMet on different types of human cancer has been widely reported in the literature, and its association with other anticancer molecules has identified the sulfonium compound as a promising biomolecule for combined anticancer therapies [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42].…”

“…Furthermore, the sulfonium compound has been shown to increase serotonin levels in the brain, similar to antidepressant drugs, but with fewer side effects [21], and clinical studies have demonstrated that AdoMet is equally effective in reducing joint pain and inflammation as nonsteroidal anti-inflammatory drugs [22]. More recently, the antiproliferative properties of AdoMet and its implication in multiple cellular processes such as proliferation, differentiation, cell cycle regulation and apoptosis in various tumor cells have been thoroughly examined in the literature [28][29][30][31][32][33][34][35][36][37][38]. It has been shown that in human osteosarcoma U2OS and LM-7 cells, treatment with AdoMet leads to a dose-dependent decrease in cell proliferation and induces the onset of apoptosis [28,29].…”

“…In head and neck squamous carcinoma (HNSC) cells, AdoMet induces cell cycle arrest and apoptosis by activating endoplasmic reticulum stress and inhibits cell migration in Cal33, JHU-SCC-011 [33,34] and HNO210 [35] cell lines. Moreover, in colon cancer cells AdoMet overcomes uL3-mediated drug resistance in p53-deleted HCT116 [36], triggers apoptosis by reduction of FLICE-like inhibitory protein expression in RKO and HT-29 cells [37] and alters tumor progression by modulating gene expression in HT-29 and SW480 cells [38].…”

S-Adenosylmethionine Increases the Sensitivity of Human Colorectal Cancer Cells to 5-Fluorouracil by Inhibiting P-Glycoprotein Expression and NF-κB Activation

“…Growing evidence accumulating in literature in recent years on the antiproliferative and proapoptotic activities exerted by AdoMet in colon cancer cells highlighted the pleiotropic effects of this eclectic multi-target sulfonium compound, evidencing its ability to modulate the genes responsible for cell invasion and metastasis [16][17][18][19][20][21][22]. In RKO and HT-29 colon cancer cells, AdoMet induced apoptosis by decreasing the expression of the gene encoding FLICE-like inhibitory protein, leading to caspase 8 activation and the consequent release of cytochrome c from the mitochondria [17].…”