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Glycobiology Advance Access published online on March 30, 2006
Glycobiology, 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. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Received July 18, 2005
Revised March 19, 2006
Accepted March 20, 2006

Article

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 Choi 1 #, Tae-Wook Chung 2 #, Sung-Koo Kang 1, Young-Choon Lee 3, Jeong-Heon Ko 4, Jong-Guk Kim 5, and Cheorl-Ho Kim 1 *

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

* To whom correspondence should be addressed.
Cheorl-Ho Kim, E-mail: chkimbio{at}skku.ac.kr


  Abstract

The simple ganglioside GM3 has been shown to have antiproliferative 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 -independent mechanisms, and tumor suppressor 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. Whereas, 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.

Keywords: Ganglioside GM3 (Neu5Ac{alpha}2,3Gal{beta}1,4Glc{beta}1,1Cer)/cell cycle/PTEN/p53/p21WAF1/MDM2/p27kip1.

#Both of these authors contributed equally to this work.


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