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Glycobiology Advance Access published online on March 29, 2006
Glycobiology, doi:10.1093/glycob/cwj103
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org
Received January 19, 2006
Revised March 7, 2006
Accepted March 17, 2006

Article

Endogenously Produced Ganglioside GM3 Endows Etoposide and Doxorubicin Resistance by Up-regulating Bcl-2 Expression in 3LL Lewis Lung Carcinoma Cells

Mariko Noguchi 1, Kazuya Kabayama 2, Satoshi Uemura 2, Byoung-won Kang 3, Masaki Saito 4, Yasuyuki Igarashi 1, and Jin-ichi Inokuchi 2 *

1 Department of Biomembrane and Biofunctional Chemistry, Hokkaido University, Japan
2 Department of Biomembrane and Biofunctional Chemistry; Core Research for Evaluational Science and Technology program (CREST), Japan Science and Technology Corporation (JST), Graduate School of Pharmaceutical Sciences, Frontier Research Center for Post-Genomic Science and Technology, Hokkaido University, Kita 21-Nishi 11, Kita-ku, Sapporo 001-0021, Japan
3 Department of Chemistry, Dong-Eui University, (San24, Gaya-dong) 995, Eomgwangno, Busan 614-714, Korea
4 Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan

* To whom correspondence should be addressed.
Jin-ichi Inokuchi, E-mail: inokuchi{at}kinou02.pharm.hokudai.ac.jp


  Abstract

The ganglioside patterns have been shown to dramatically change during cell proliferation and differentiation and in certain cell cycle phases, brain development, and cancer malignancy. To investigate the significance of the ganglioside GM3 in cancer malignancy, we established GM3- reconstituted cells by transfecting the cDNA of GM3 synthase (SAT-I) into a GM3-deficient subclone of the 3LL Lewis lung carcinoma cell line (Uemura et al., 2003). The GM3-reconstituted cells were resistant to apoptosis induced by etoposide and doxorubicin. There were no changes in the expression levels of topoisomerase II{alpha} or P-glycoprotein, or in the uptake of doxorubicin between the GM3-reconstituted cells and the mock-transfected cells. To understand the mechanism of the etoposide-resistant phenotype acquired in the GM3-reconstituted cells, we investigated their apoptotic signaling. Although no difference was observed in the phosphorylation of p53 at Ser15 site (p53-Ser15) by etoposide between the GM3-reconstituted cells and mock-transfected cells, the activation of both caspase-3 and caspase-9 was specifically inhibited in the former. We found that the anti-apoptotic protein Bcl-2 was increased in the GM3-reconstituted cells. Moreover, wild type 3LL Lewis lung carcinoma cells, which have an abundance of GM3 exhibited no DNA fragmentation following etoposide treatment and expressed higher levels of the Bcl-2 protein compared with the J5 subclone. Thus, these results support the conclusion that endogenously produced GM3 is involved in malignant phenotypes, including anti-cancer drug resistance through up-regulating the Bcl-2 protein in this lung cancer cell line.


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