ABSTRACT
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common fatal cancer in people younger than 20 years of age. This study was designed to explore the anti-leukemia activity of physcion 8-O-ß-glucopyranoside (PG) in B-cell ALL. METHODS: NALM6 and SupB15 cells were used as model cell lines. Cell viability, cell apoptosis, cell cycle distribution were determined by CCK-8 assay, DNA fragmentation assay and flow cytometry, and flow cytometry, respectively. Expression of proteins involved in cell apoptosis and cell cycle regulation was determined by western blot and the levels of ceramide and sphingosine 1-phosphate (S1P) were determined by ELISA. Activity of sphingosine kinase 1 (SphK1) was also determined with a Sphingosine Kinase Assay Kit. In the present study, both model cell lines were transfected with siRNA targeting SphK1 or an overexpression plasmid to examine the role of SphK1 in the anti-leukemia activity of PG. Moreover, the efficacy of PG was examined in vivo in a mouse model by measuring survival and spleen weight. RESULTS: Our results provided experimental evidence that PG could significantly induce apoptosis and cell cycle arrest in vitro. Mechanistically, the anti-leukemia activity of PG was mediated by its ability to repress SphK1 and thus modulate ceramide-S1P rheostat. Moreover, the anti-leukemia activity of PG was also verified in a murine model. CONCLUSION: Collectively, our results indicate that PG may be a promising agent for the treatment of B-cell leukemia.
Subject(s)
Emodin/analogs & derivatives , Glucosides/pharmacology , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Animals , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Ceramides/metabolism , DNA Damage/drug effects , Emodin/pharmacology , Humans , Lysophospholipids/metabolism , Mice , Mice, Knockout , RNA, Small Interfering/pharmacology , Sphingosine/analogs & derivatives , Sphingosine/metabolismABSTRACT
Histone methyltransferases are important determinants of the initiation and progression of hepatocellular carcinoma (HCC) and represent promising therapeutic targets. However, whether the expression profile of multiple histone methyltransferases represents a poorer prognosis is entirely unknown. The aim of the present study was to investigate the association between histone methylation and HCC phenotype, and the prognostic value of combining expression levels of SET domain-containing protein 8 (SET8) with protein arginine methyltransferase 5 (PRMT5) in patients with HCC following curative resection. The retrospective study included 195 consecutive patients who had undergone hepatectomy for HCC. Immunohistochemical staining for SET8 and PRMT5 was performed on paraffin-embedded tumor tissue microarrays. Expression was analyzed for correlations with clinicopathological features, marker co-expression and patients' survival by univariate and multivariate analyses. Positive SET8 expression was noted in 104 patients (53.3%), and was associated with PRMT5 expression (n=106, 54.4%, P<0.05). Immunohistochemical analysis demonstrated that high expression of SET8 and PRMT5 was significantly associated with poor overall survival (OS, P<0.001) and time to recurrence (TTR, P<0.001). Multivariate Cox analysis revealed that SET8 and PRMT5, along with vascular invasion, tumor size and tumor number, were independent prognostic factors for OS and TTR. The combination of SET8 and PRMT5 demonstrated an improved capacity to predict patient mortality and disease recurrence (P=0.002 and P=0.004, respectively), particularly for the prediction of early recurrence (P<0.001). In conclusion, high expression of SET8 combined with PRMT5 was associated with a high rate of recurrence and poor survival in patients with HCC. The independent pattern of histone methylation represents a novel insight into tumor progression and therapeutic targets for HCC.