S-Adenosylmethionine regulates apoptosis and autophagy in MCF-7 breast cancer cells through the modulation of specific microRNAs

Abstract

BackgroundTo get insight into the molecular mechanisms underlying the anti-tumor activity of S-adenosyl-l-methionine (AdoMet), we analyzed AdoMet-induced modulation of microRNAs (miRNAs) expression profile in MCF-7 breast cell line and its correlation with cancer-related biological pathways.MethodsMiRNA expression profiling was performed using a TaqMan MiRNA Array, following 500 µM AdoMet-treatment. The results were confirmed by Quantitative real-time PCR analysis. MCF-7 were transfected with miR-34a, miR-34c and miR-486-5p, mimics and inhibitors in presence or not of 500 µM AdoMet for 72 h. Apoptosis and autophagy were analyzed by flow cytometry and the modulation of the main antiproliferative signaling pathways were evaluated by Western blotting. The potential mRNA targets for each miRNA were identified by the TargetScan miRNA target prediction software.ResultsTwenty-eight microRNAs resulted differentially expressed in AdoMet-treated MCF-7 cells compared to control cells. Among them, miRNA-34a and miRNA-34c were up-regulated while miRNA-486-5p was down-regulated. Moreover, we confirmed the ability of AdoMet to regulate these miRNAs in MDA-MB 231 breast cancer cell line. We demonstrate that, in MCF7 cells, the combination of either miR-34a or miR-34c mimic with AdoMet greatly potentiated the pro-apoptotic effect of AdoMet, by a caspase-dependent mechanism and activates p53 acetylation by inhibiting SIRT1 and HDAC1 expression. We also showed that miR-486-5p inhibitor induces autophagy and enhances AdoMet-induced autophagic process by increasing PTEN expression and by inhibiting AKT signaling.ConclusionsOur findings provide the first evidence that AdoMet can regulate miRNA expression in MCF-7 increasing our knowledge on the molecular basis of the antitumor effect of the sulfonium compound and suggest the use of AdoMet as an attractive miRNA-mediated chemopreventive and therapeutic strategy in breast cancer.

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

“…MiRNA-34c and miRNA-449a, that belong to miRNA-34/449 superfamily, share several target genes and a very similar seed sequence, a conserved heptameric sequence comprising nucleotides 2–7 at the 5′ end of the miRNA, essential for binding to target mRNA [ 44 , 45 , 46 , 47 ]. MiRNA-34c and miRNA-449a are downregulated in a wide range of cancers, including human breast cancer suggesting their function as potential tumor suppressors [ 43 , 44 , 45 , 46 , 47 ]. Notably, the up-regulation of miRNA-34 and miRNA-449 has been demonstrated to regulate oncogenic pathways including cell proliferation, metastases and apoptotic pathways [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ].…”

“…Our research group has thoroughly investigated the antiproliferative and proapoptotic role exerted by AdoMet in breast cancer [ 24 , 41 , 42 ] and recently provided the first evidence that in hormone-positive breast cancer cells AdoMet is able to regulate the expression of miRNA-34a, miRNA-34c, and miRNA-486-5p which play a crucial role in the development and maintenance of the tumor cell phenotype [ 43 ].…”

LINC02418 promotes colon cancer progression by suppressing apoptosis via interaction with miR-34b-5p/BCL2 axis

“…Bioinformatic analysis revealed that LINC02418 and 3'UTR region of BCL2 contained complementary sequence of miR-34b-5p, implying miR-34b-5p could bind to LINC02418 and BCL2 gene. MiR-34b-5p belongs to the miR-34 family which has been reported to be tumor suppressor and therapeutic candidate in cancer [33][34][35][36]. Dual-luciferase activity assays con rmed the interaction between miR-34b-5p and LINC02418 (Fig.…”

Mi-RNA-888-5p Is Involved in S-Adenosylmethionine Antitumor Effects in Laryngeal Squamous Cancer Cells

“…In a recent work, it was demonstrated that, in hepatocellular carcinoma, the reduction in the expression of methionine adenosyltransferase genes, coding the enzyme that synthesizes AdoMet can be attributed to the regulation of miRNAs, resulting in decreased AdoMet levels and the deregulation of signal transduction pathways correlated to methionine metabolism and methionine adenosyltransferase activity [21]. In MCF-7 breast cancer cells, we have demonstrated that AdoMet induces apoptosis and autophagy by the regulation of the expression of miR-34a, miR-34c and miR-486-5p [22].…”