Abstract
ABSTRACTBackground: Diallyl trisulfide (DATS), a bioactive sulfur compound in garlic, has been highlighted due to its strong anti-carcinogenic activity.Objective: The current study investigated the molecular mechanism of garlic-derived DATS in cancer cells. Additionally, we explored possible molecular markers to monitoring clinical responses to DATS-based chemotherapy.Design: EJ bladder carcinoma cells were treated with different concentration of DATS. Molecular changes including differentially expressed genes in EJ cells were examined using immunoblot, FACS cell cycle analysis, migration and invasion assays, electrophoresis mobility shift assay (EMSA), microarray, and bioinformatics analysis.Results: DATS inhibited EJ cell growth via G2/M-phase cell cycle arrest. ATM-CHK2-Cdc25c-p21WAF1-Cdc2 signaling cascade, MAPKs, and AKT were associated with the DATS-mediated growth inhibition of EJ cells. DATS-induced inhibition of migration and invasion was correlated with down-regulated MMP-9 via reduced activation of AP-1, Sp-1, and NF-κB. Through microarray gene expression analysis, ANGPTL4, PLCXD1, and MMP3 were identified as candidates of molecular targets of DATS. Introduction of each gene to EJ cells revealed that ANGPTL4 was associated with the DATS-induced inhibition of cell growth, migration, and invasion.Conclusions: ANGPTL4 regulates DATS-mediated inhibition of proliferation, migration, and invasion of EJ cells, and thus, has potential as a prognostic marker for bladder cancer patients.
Highlights
Bladder cancer is one of the most common cancers of the human genitourinary system worldwide
We investigated the mechanism of Diallyl trisulfide (DATS)-mediated inhibition of proliferation, migration, and invasion of EJ bladder cancer cells through comprehensive analysis of signaling pathways, cell cycle regulation, and transcription factor-associated MMP-9 regulation
As concentrations of DATS increased, accumulation at G2/M phase increased proportionally (Figure 1(d–h)). These results showed that DATS inhibits proliferation of EJ cells through a mechanism involving G2/M phase cell-cycle arrest
Summary
Bladder cancer is one of the most common cancers of the human genitourinary system worldwide. The development of new therapeutic options is crucial to long-term survival of bladder cancer patients. Allicin is very unstable and is readily converted into sulfur-containing compounds such as diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), and other allyl polysulfides [3,5]. These organic sulfur compounds have attracted great attention as a novel pool of cancer preventive agents [3,5]. Objective: The current study investigated the molecular mechanism of garlic-derived DATS in cancer cells. Molecular changes including differentially expressed genes in EJ cells were examined using immunoblot, FACS cell cycle analysis, migration and invasion assays, electrophoresis mobility shift assay (EMSA), microarray, and bioinformatics analysis
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