S-Adenosylmethionine Inhibits Colorectal Cancer Cell Migration through Mirna-Mediated Targeting of Notch Signaling Pathway

Abstract

Metastasis is a leading cause of mortality and poor prognosis in colorectal cancer (CRC). Thus, the identification of new compounds targeting cell migration represents a major clinical challenge. Recent findings evidenced a central role for dysregulated Notch in CRC and a correlation between Notch overexpression and tumor metastasis. MicroRNAs (miRNAs) have been reported to cross-talk with Notch for its regulation. Therefore, restoring underexpressed miRNAs targeting Notch could represent an encouraging therapeutic approach against CRC. In this context, S-adenosyl-L-methionine (AdoMet), the universal biological methyl donor, being able to modulate the expression of oncogenic miRNAs could act as a potential antimetastatic agent. Here, we showed that AdoMet upregulated the onco-suppressor miRNAs-34a/-34c/-449a and inhibited HCT-116 and Caco-2 CRC cell migration. This effect was associated with reduced expression of migration-/EMT-related protein markers. We also found that, in colorectal and triple-negative breast cancer cells, AdoMet inhibited the expression of Notch gene, which, by luciferase assay, resulted the direct target of miRNAs-34a/-34c/-449a. Gain- and loss-of-function experiments with miRNAs mimics and inhibitors demonstrated that AdoMet exerted its inhibitory effects by upregulating miRNAs-34a/-34c/-449a. Overall, these data highlighted AdoMet as a novel Notch inhibitor and suggested that the antimetastatic effects of AdoMet involve the miRNA-mediated targeting of Notch signaling pathway.

Desulfovibrio desulfuricans and its derived metabolites confer resistance to FOLFOX through METTL3

“… 29 SAM has also upregulated miRNAs to suppress CRC cell migration. 30 These findings differ from those of our study. In light of these disparities, we suggest that the dosage of SAM administered to the colon cancer cells may have contributed to these discrepancies.…”

Characteristics of amino acid metabolism in colorectal cancer

“…We found that SAM significantly reduced vimentin levels and promoted the transformation from N-cadherin to E-cadherin expression in HCT-116 and Caco-2 cells, as demonstrated by comparing the strength of corresponding protein bands in SAM treated and untreated cells. This highlights the ability of SAM to slow CRC cell migration by inhibiting the transition from epithelial to mesenchymal states[ 33 ]. SAM inhibits CRC cell growth by reversing the hypomethylation of c-Myc and H-ras promoters, thereby inhibiting the expression of these oncogenes[ 34 ].…”

Antitumoral Activity of the Universal Methyl Donor S-Adenosylmethionine in Glioblastoma Cells

“…Increasing evidence has also demonstrated that the epigenetic regulation of oncogenic or tumor-suppressor microRNAs represents one of the main mechanisms underlying the anticancer activity of AdoMet [30,[35][36][37][38].…”