Abstract
Our recent report showed that curcumin, polyphenolic compound isolated from the herb Curcuma longa, upregulated the gene expression of human GD3 synthase (hST8Sia I) responsible for ganglioside GD3 synthesis with autophagy induction in human lung adenocarcinoma A549 cells. In this study, on the contrary to this finding, we demonstrated that curcumin downregulated the gene expression of human GM3 synthase (hST3Gal V) catalyzing ganglioside GM3 synthesis with autophagy induction in human colon carcinoma HCT116 cells. To clarify the mechanism leading to the downregulation of hST3Gal V gene expression in curcumin-treated HCT116 cells, we analyzed the curcumin-inducible promoter of the hST3Gal V gene by luciferase reporter assays. Promoter deletion analysis demonstrated that the -177 to -83 region, which includes putative binding sites for transcription factors NFY, CREB/ATF, SP1, EGR3, and MZF1, acts as the curcumin-responsive promoter of the hST3Gal V gene. Site-directed mutagenesis and chromatin immunoprecipitation analysis demonstrated that the CREB/ATF binding site at -143 is pivotal for curcumin-induced downregulation of hST3Gal V gene in HCT116 cells. The transcriptional activation of hST3Gal V in HCT116 cells was significantly repressed by an inhibitor of AMP-activated protein kinase (AMPK). These results suggest that AMPK signal pathway mediates hST3Gal V gene expression in HCT116 cells.
Highlights
Gangliosides, the sialylated glycosphingolipids, are components of lipid rafts along with sphingomyelin and cholesterol as well as a part of the glycocalyx in mammalian cells [1, 2]
Promoter activity of pGL3-177 as a control was significantly suppressed in curcumin-treated HCT116 cells, compared with untreated HCT116 cells. This pattern was not significantly affected by LY294002 (PI3K/AKT inhibitor), U0126 (MEK/ERK inhibitor), SP600125 (JNK inhibitor), and SB203580 (p38 MAPK inhibitor), whereas compound C (AMPK inhibitor) treatment resulted in a 50% decrease in promoter activity. These results indicate that transcriptional activation of hST3Gal V gene in HCT116 cells is mediated by AMP-activated protein kinase (AMPK) signaling pathway
We have previously demonstrated that transcriptional activation of the hST3Gal V gene by TPA in HL60 cells occurs through PKC/ ERKs signal transduction pathway [17], whereas JNKs signaling pathway is associated with transcriptional activation of the hST3Gal V gene by valproic acid in ARPE-19 cells [14]
Summary
Gangliosides, the sialylated glycosphingolipids, are components of lipid rafts along with sphingomyelin and cholesterol as well as a part of the glycocalyx in mammalian cells [1, 2] Their biosynthesis occurs through stepwise addition of carbohydrate residues from their nucleotide sugar donors to the growing glycan by a series of specific glycosyltransferases in the Golgi apparatus [3, 4]. They are expressed in a cell typespecific and stage-specific manner and play crucial roles in numerous cellular events, including cell-cell interaction, cell differentiation, adhesion, signal transduction, and oncogenesis [4,5,6,7]. The roles of exogenous ganglioside in autophagy induction are known, no studies have been reported on the molecular mechanisms responsible for gene expression of ganglioside synthases catalyzing ganglioside biosynthesis during autophagy induction
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