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Ganglioside GM3 inhibits growth of several cancer cells and induces cell cycle arrest by regulating cellular signal pathways. Previously, we showed that GM3 suppresses tumor suppressor PTEN-mediated cancer cell proliferation and increases the PTEN expression and the accumulation of p53 protein by the PTEN-mediated inhibition of the PI-3K/Akt/Mdm2 signaling pathway in HCT116 colorectal cancer cells, confirming that GM3 functions as the p53 protein stabilizer. Consequently, GM3 induces p53-depentent cyclin-dependent kinase (CDK) inhibitor (CKI) p21WAF1 expression in the wild type of p53-positive HCT116 colorectal cancer cells, but not in the p53-negative HCT116 cells lacking p53 (HCT116 p53-/-). Moreover, the data herein clearly show that GM3 induces the production of the CDK inhibitor p21WAF1 at the transcriptional level, as evidenced by the p21WAF1 promoter-driven luciferase reporter plasmid (full-length p21WAF1 promoter and a construct lacking the p53 binding sites). Furthermore, the down-regulation of the cyclin E/CDK2 complex as well as the up-regulation of the CDK inhibitor p21WAF1 were clearly observed in GM3-treated HCT116 cells, but the down-regulation of cyclin D1/CDK4 was not. These results suggest that GM3 induces PTEN gene expression and p53-dependent p21WAF1 accumulation, thus leading to cell cycle arrest. On the other hand, GM3 induces transcription factor AP-2α-mediated PTEN expression in colon cancer cells. The enhanced expression of PTEN by GM3 in both HCT116 and p53-null HCT116 cells has been shown to be not associated with p53 function. Thus, to further determine the mechanism underlying the regulation of PTEN gene expression by GM3, we characterized the promoter region of the PTEN gene. Promoter analysis of the 5’-flanking region of the PTEN gene showed that region between -1175 and -1077 from translational initiation site, which contains AP-2α binding site, functions as the GM3-inducible promoter in colon cancer cells. Furthermore, gel shift assays, site-directed mutagenesis and chromatin immunoprecipitation assay obviously indicated that the AP-2α is essential for the expression of PTEN in GM3-stimulated colon cancer cells. Moreover, siRNA against AP-2α diminished the enhancement of AP-2α and PTEN expression in GM3-induced colon cancer cells. The transient expression of AP-2α also results in the induction of PTEN transcription in AP-2α-negative colon cancer cells. Additionally, GM3 induced AP-2α-mediated PTEN expression through the inhibition of autocrine-ligand-mediated EGFR activation. These results suggest that the AP-2α transcription factor is required for the ganglioside GM3-stimulated transcriptional regulation of PTEN gene [Choi et al., 2008, Glycobiology]. Using phage display method, we have found for the first time that GM3 directly interacts with VEGFR-2, which inhibits VEGF/VEGFR-2-mediated biological function of vascular endothelial cell and angiogenesis both in vitro and in vivo, the growth of primary tumors in mice inoculated with tumor cells and VEGF-stimulated microvessel permeability in mouse skin capillaries. These results suggest that GM3 are angiogenic inhibitor, and might be a therapeutic avenue for anti-angiogenesis and that GM3 represents a physiological modulator of cancer cell proliferation and, therefore, may have potential for use in colorectal cancer therapy.

저자

• Tae-Wook Chung [ Molecular and Cellular Glycobiology Unit, Department of Biological Science, SungKyunKwan University ]
• Seok-Jo Kim [ Molecular and Cellular Glycobiology Unit, Department of Biological Science, SungKyunKwan University ]
• Cheorl-Ho Kim [ Molecular and Cellular Glycobiology Unit, Department of Biological Science, SungKyunKwan University ]

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• 간행물명

  한국당과학회 학술대회

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  연간

• 수록기간

  2006~2022

• 십진분류

  KDC 517 DDC 614