Iron Metabolism as a Potential Mechanism for Inducing TRAIL-Mediated Extrinsic Apoptosis Using Methylsulfonylmethane in Embryonic Cancer Stem Cells

Abstract

Embryonic cancer stem cells (CSCs) can differentiate into any cancer type. Targeting CSC using natural compounds is a good approach as it suppresses cancer recurrence with fewer adverse effects, and methylsulfonylmethane (MSM) is a sulfur-containing compound with well-known anticancer activities. This study determined the mechanistic aspects of the anticancer activity of MSM. We used Western blotting and real-time qPCR for molecular signaling studies and conducted flow cytometry for analyzing the processes in cells. Our results suggested an inhibition in the expression of CSC markers and Wnt/β-catenin signaling. MSM induced TRAIL-mediated extrinsic apoptosis in NCCIT and NTERA-2 cells rather than an intrinsic pathway. Inhibition of iron metabolism-dependent reactive oxygen species (ROS) generation takes part in TRAIL-mediated apoptosis induction by MSM. Suppressing iron metabolism by MSM also regulated p38/p53/ERK signaling and microRNA expressions, such as upregulating miR-130a and downregulating miR-221 and miR-222, which resulted in TRAIL induction and thereby extrinsic pathway of apoptosis. Hence, MSM could be a good candidate for neoadjuvant therapy by targeting CSCs by inhibiting iron metabolism.

Mechanism of action of CTRP6 in the regulation of tumorigenesis in the digestive system (Review)

“…Additionally, in a recent study, Zhang et al ( 77 ) proposed that microRNA (miR)-148a inhibited HCC cell growth by targeting death receptors and downregulating epithelial-to-mesenchymal transition and PI3K/Akt signaling pathways. Moreover, methylsulfonylmethane inhibits iron metabolism and modulates p38/p53/ERK signaling and miR expression targeted to inhibit the proliferation of embryonic cancer stem cells ( 78 ). These studies suggest that miRs are likely to be involved in the regulation of CTRPs in gastrointestinal tumors, miRs may be involved in the regulation of CTRPs on gastrointestinal tumors by activating the PI3K/Akt pathway.…”