The hyaluronic acid inhibitor 4-methylumbelliferone is an NSMase2 activator—role of Ceramide in MU anti-tumor activity

Abstract

Increased synthesis of hyaluronic acid (HA) is often associated with increased metastatic potential and invasivity of tumor cells. 4-Methylumbelliferone (MU) is an inhibitor of HA synthesis, and has been studied as a potential anti-tumor drug to inhibit the growth of primary tumors and distant metastasis of tumor cells. Although several studies reported that the anticancer effects of MU are mediated by inhibition of HA signaling, the mechanism still needs to be clarified. In a previous study we demonstrated the regulation of HA synthesis by ceramide, and now show how MU activated neutral sphingomelinase2 (NSMase2), generates ceramides and mediates MU induced inhibition of HA synthesis, cell migration and invasion, and apoptosis of tumor cells. Using a HA enriched mouse oligodendroglioma cell line G26-24 we found that MU elevated the activity of NSMase2 and increased ceramide levels, which in turn increased phosphatase PP2A activity. Further, the activated PP2A reduced phosphorylation of Akt, decreased activities of HA synthase2 (HAS2) and calpains, and inhibited both the synthesis of HA, and the migration and invasion of G26-24 tumor cells. In addition, MU mediated ceramide stimulated activation of p53 and caspase-3, reduced SIRT1 expression and decreased G26-24 viability. The mechanism of the MU anticancer therefore initially involves NSMase2/ceramide/PP2A/AKT/HAS2/caspase-3/p53/SIRT1 and the calpain signaling pathway, suggesting that ceramides play a key role in the ability of a tumor to become aggressively metastatic and grow.

Sphingomyelin phosphodiesterase 3 methylation and silencing in oral squamous cell carcinoma results in increased migration and invasion and altered stress response

“…While previous studies found that SMPD3 overexpression was sufficient to slow the proliferation rate of various cancer cell lines, including the breast cancer line MCF-7, the osteosarcoma line F4328, and the hepatocellular carcinoma line JHH-7, we found no effect on proliferation of either oral dysplasia or OSCC cell lines [20,21,27]. However, our data suggest that SMPD3 does inhibit the capacity of cells for migration and invasion, in agreement with previous studies [30].…”

Exosomal PD-L1 Derived From Osteosarcoma is Associated With Pulmonary Metastasis for Patients With Osteosarcoma

“…Thus, suppression of exosomal PD-L1 may be a promising personalized therapy. It has been reported that GW4869 could decrease the secretion of tumor cell exosome, which inhibit the cell growth [51]. Although we can not observe the signi cantly inhibiting effect of GW4869 on the osteosarcoma cell growth in vitro in the present study, inhibition of exosome secretion by GW4869 could suppress the pulmonary metastasis in vivo study.…”

Quantum dot‐mediated delivery of siRNA to inhibit sphingomyelinase activities in brain‐derived cells

“…We chose SMases knockdown to demonstrate the utility of the QD approach because they are enzymes activated in the CNS following various kinds of stress (Qin et al . , , ; Qin and Dawson ). Knockdown efficiency by QD‐siRNA was roughly comparable to a commercially siRNA delivery lipofection kit but without the cytotoxicity.…”

“…Moreover, siRNA was delivered in sufficient quantities as to effect a substantial change in enzyme expression as shown by luciferase and sphingomyelinase assay. We chose SMases knockdown to demonstrate the utility of the QD approach because they are enzymes activated in the CNS following various kinds of stress (Qin et al 2009(Qin et al , 2015. Knockdown efficiency by QD-siRNA was roughly comparable to a commercially siRNA delivery lipofection kit but without the cytotoxicity.…”