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Glycobiology Advance Access originally published online on March 30, 2006
Glycobiology 2006 16(7):573-583; doi:10.1093/glycob/cwj105
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.
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Ganglioside GM3 modulates tumor suppressor PTEN-mediated cell cycle progression—transcriptional induction of p21WAF1 and p27kip1 by inhibition of PI-3K/AKT pathway

Hee-Jung Choi2,*, Tae-Wook Chung2,3,*, Sung-Koo Kang2, Young-Choon Lee4, Jeong-Heon Ko5, Jong-Guk Kim3 and Cheorl-Ho Kim1,2

2 Molecular and Cellular Glycobiology Unit, Department of Biological Science, Sungkyunkwan University, 300 Chunchun-Dong, Jangan-Gu, Suwon City, Kyunggi-Do 440-746, South Korea; 3 Department of Microbiology, Kyungpook National University, Daegu 702-701, South Korea; 4 Faculty of Biotechnology, Dong-A University, Saha-Gu, Busan 604-714, South Korea; and 5 Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-600, South Korea

1 To whom correspondence should be addressed; e-mail: chkimbio{at}skku.ac.kr

Received on July 18, 2005; revised on March 19, 2006; accepted on March 20, 2006

The simple ganglioside GM3 has been shown to have anti-proliferative effects in several in vitro and in vivo cancer models. Although the exogenous ganglioside GM3 has an inhibitory effect on cancer cell proliferation, the exact mechanism by which it prevents cell proliferation remains unclear. Previous studies showed that MDM2 is an oncoprotein that controls tumorigenesis through both p53-dependent and p53-independent mechanisms, and tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a dual-specificity phosphatase that antagonizes phosphatidylinositol 3-kinase (PI-3K)/AKT signaling, is capable of blocking MDM2 nuclear translocation and destabilizing the MDM2 protein. Results from our current study show that GM3 treatment dramatically increases cyclin-dependent kinase (CDK) inhibitor (CKI) p21WAF1 expression through the accumulation of p53 protein by the PTEN-mediated inhibition of the PI-3K/AKT/MDM2 survival signaling in HCT116 colon cancer cells. Moreover, the data herein clearly show that ganglioside GM3 induces p53-dependent transcriptional activity of p21WAF1, as evidenced by the p21WAF1 promoter-driven luciferase reporter plasmid (full-length p21WAF1 promoter and a construct lacking the p53-binding sites). Additionally, ganglioside GM3 enhances expression of CKI p27kip1 through the PTEN-mediated inhibition of the PI-3K/AKT signaling. Furthermore, the down-regulation of the cyclin E and CDK2 was clearly observed in GM3-treated HCT116 cells, but the down-regulation of cyclin D1 and CDK4 was not. On the contrary, suppression of PTEN levels by RNA interference restores the enhanced expression of p53-dependent p21WAF1 and p53-independent p27kip1 through inactivating the effect of PTEN on PI-3K/AKT signaling modulated by ganglioside GM3. These results suggest that ganglioside GM3-stimulated PTEN expression modulates cell cycle regulatory proteins, thus inhibiting cell growth. We conclude that ganglioside GM3 represents a modulator of cancer cell proliferation and may have potential for use in colorectal cancer therapy.

Key words: ganglioside GM3 (Neu5Ac{alpha}2,3Galß1,4Glcß1,1Cer) / MDM2 / p21WAF1 / p27kip1 / PTEN

* These authors contributed equally to this work.


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