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.
Highlights
Embryonic stem (ES) cells can differentiate into all derivatives of embryonic germ layers, ectoderm, endoderm, and mesoderm, whereas embryonic cancer stem cells (CSCs) have these abilities along with uncontrolled proliferation, making them more dangerous than other cancer cells [1,2]
Sex-determining region Y (SRY)-box 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and homeobox protein NANOG were overexpressed in CSC, helping to promote tumorigenesis, and they can maintain the pluripotent nature of CSC [9,10]
This study demonstrated the effect of MSM in iron metabolism and its role in TRAILmediated extrinsic apoptosis in NCCIT and NTERA-2 embryonic CSCs
Summary
Embryonic stem (ES) cells can differentiate into all derivatives of embryonic germ layers, ectoderm, endoderm, and mesoderm, whereas embryonic cancer stem cells (CSCs) have these abilities along with uncontrolled proliferation, making them more dangerous than other cancer cells [1,2]. In canonical Wnt signaling, secreted glycoprotein Wnt family proteins along with β-catenin, a transcription activator factor for the Wnt family, promote homeostasis and embryonic development [7]. Along with Wnt/β-catenin signaling, CSC markers play a key role in developing CSC. Sex-determining region Y (SRY)-box 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and homeobox protein NANOG were overexpressed in CSC, helping to promote tumorigenesis, and they can maintain the pluripotent nature of CSC [9,10]. Targeting these Wnt/β-catenin signaling and CSC markers is an effective treatment method against CSC and targets cancer cells [11,12]
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