Expression of Nur77 induced by an n-butylidenephthalide derivative promotes apoptosis and inhibits cell growth in oral squamous cell carcinoma

Abstract

In spite of numerous advances, the 5-year survival rate for head and neck squamous cell cancer has remained largely stagnant and few new anti-tumor drugs have been developed. PCH4, a derivative of n-butylidenephthalide, has been investigated for its anti-tumor effects on oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the anti-tumor mechanism of a potential target gene, Nur77, in OSCC cells, which can be induced by PCH4 treatment. Data show that PCH4 promoted Nur77 translocation from the nucleus to the cytoplasm and induced cell apoptosis in OSCC cells. When Nur77 translocation was blocked, the degree of tumor apoptosis caused by PCH4 was significantly inhibited (p < 0.05). Within the MAPK pathway, PCH4 only induced JNK phosphorylation. Furthermore, treatment with a JNK inhibitor significantly reduced PCH4-induced apoptosis (p < 0.05) and decreased PCH4-induced Nur77 expression (p < 0.05). In a xenograft animal model, administration of PCH4 also showed anti-tumor effects. We have demonstrated that OSCC cells are sensitive to PCH4 and that Nur77 protein translocation from the nucleus to the cytoplasm might be associated with the induction of apoptosis by PCH4. These results indicate that PCH4 may serve as a potential anti-tumor drug for OSCC therapy.

Exploring the mechanism of WWOX growth inhibitory effects on oral squamous cell carcinoma

“…In OSCC, NR4A1 activated through the MAPK signaling pathway can induce apoptosis (23). The present study demonstrated that the combination of the upregulation of NR4A1 and MAP2K5 increased the level of apoptosis subsequent to WWOX overexpression in Tca8113 cells.…”

Neuroprotective and Cytotoxic Phthalides from Angelicae Sinensis Radix

“…Their ability to produce structurally diverse and biologically significant monomeric and dimeric phthalide metabolites is well documented [1,2]. Previous pharmacological activity studies revealed that these compounds display anti-proliferative [3,4], anti-inflammatory [5][6][7], anti-thrombus [8], neuroprotective [9][10][11], anti-tumor [12,13], and anti-spasmodic effects. In recent years, the bioactivities of these compounds have attracted a great interest and extensive research has been carried out to characterize the molecular mechanism(s) behind their activity.…”

NR4A1 (nuclear receptor subfamily 4, group A, member 1)

“…For example, in response to n-Butylidenephthalide induced cell death signals, NR4A1 translocates into mitochondria to enhance apoptosis Liu et al, 2012).…”

“…For example, glioblastoma multiforme is inhibited by local interstitial delivery of z-butylidenephthalide, which enhances NR4A1 expression and translocation into mitochondria Lin et al, 2008). Nbutylidenephthalide derivative also inhibit cell growth in hepatocellular carcinoma, oral squamous cell carcinoma and balloon injured rat carotid artery by inducing apoptosis Liu et al, 2011;Liu et al, 2012). Moreover, 1,1-Bis(3'-indolyl)-1-(psubstituted phenyl)methanes induce apoptosis through NR4A1 activation in cultured pancreatic carcinoma cells (Chintharlapalli et al, 2005).…”