sphingosine-kinase and triptolide

Triptolide (TP) exhibits effective activity against colon cancer in multiple preclinical models, but the mechanisms underlying the observed effects are not fully understood. Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid involved in the regulation of colon cancer progression. The aim of this study was to investigate the effect of TP on the sphingosine kinase (SPHK)-S1P signaling pathway in colitis-associated colon cancer.. An azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model and the THP-1 cell line were used to evaluate the therapeutic effects and mechanisms of TP in colitis-associated colon cancer (CACC). Various molecular cell biology experiments, including Western blotting, real-time PCR and immunofluorescence, were used to obtain relevant experimental data. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was also established to detect the levels of S1P in tissue and plasma.. In the AOM/DSS mouse model, TP treatment induced a dose-dependent decrease in tumor incidence and inhibited macrophage recruitment and M2 polarization in the tumors. TP also efficiently decreased the S1P levels and SPHK1/S1PR1/S1PR2 expression and significantly inhibited activation of the S1P-mediated phosphorylation of ERK protein in macrophages.. The results indicated that TP might influence the recruitment and polarization of tumor-associated macrophages by suppressing the SPHK-S1P signaling pathway.

Topics: Animals; Azoxymethane; Colitis; Colitis-Associated Neoplasms; Colon; Dextran Sulfate; Disease Models, Animal; Diterpenes; Epoxy Compounds; Female; Humans; Lysophospholipids; Male; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Nude; Phenanthrenes; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingosine; THP-1 Cells; Tumor-Associated Macrophages