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

Abstract

(1) Purpose: The methyl donor S-Adenosylmethionine (AdoMet) has been widely explored as a therapeutic compound, and its application-alone or in combination with other molecules-is emerging as a potential effective strategy for the treatment and chemoprevention of tumours. In this study, we investigated the antitumor activity of AdoMet in Laryngeal Squamous Cell Carcinoma (LSCC), exploring the underlying mechanisms. (2) Results: We demonstrated that AdoMet induced ROS generation and triggered autophagy with a consistent increase in LC3B-II autophagy-marker in JHU-SCC-011 and HNO210 LSCC cells. AdoMet induced ER-stress and activated UPR signaling through the upregulation of the spliced form of XBP1 and CHOP. To gain new insights into the molecular mechanisms underlying the antitumor activity of AdoMet, we evaluated the regulation of miRNA expression profile and we found a downregulation of miR-888-5p. We transfected LSCC cells with miR-888-5p inhibitor and exposed the cells to AdoMet for 48 and 72 h. The combination of AdoMet with miR-888-5p inhibitor synergistically induced both apoptosis and inhibited cell migration paralleled by the up-regulation of MYCBP and CDH1 genes and of their targets. (3) Conclusion: Overall, these data highlighted that epigenetic reprogramming of miRNAs by AdoMet play an important role in inhibiting apoptosis and migration in LSCC cell lines.

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].…”

“…Recently, regulation of miRNA's expression profile by AdoMet has been evaluated in breast [84,85] and in head and neck cancer cells [35], providing evidence that the ability of the sulfonium compound to inhibit proliferation and cell migration, as well as to induce apoptosis in these tumor cells, is mediated by miRNAs.…”

“…Our research group thoroughly investigated the antiproliferative and proapoptotic role exerted by AdoMet in laryngeal squamous cancer cells (LSCC), providing evidence that AdoMet is able to regulate the expression of sixteen miRNAs including miR-888-5p, an oncogenic miRNA that plays a crucial role in the development and maintenance of the tumor cell phenotype, which resulted in significantly downregulated JHU-SCC-011 and HNO210 LSCC cell lines [35]. Combined treatment of AdoMet with miR-888-5p inhibitor synergistically enhanced apoptosis and inhibited tumor cell migration induced by the sulfonium compound, indicating that the proapoptotic and antimetastatic activity of AdoMet in LSCC is mediated by the downregulation of the oncogenic miR-888-5p.…”

“…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 breast cancer cells, AdoMet reduces cell viability and induces apoptosis by activating authophagy in MCF-7 cells [30] and by enhancing Fas/FasL in CG5 cells [31] and attenuates proliferation, invasion, and metastasis in vivo in the MDA-MB-231 xenograft model [32]. 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].…”