Article

Endogenously produced ganglioside GM3 endows etoposide and doxorubicin resistance by up-regulating Bcl-2 expression in 3LL Lewis lung carcinoma cells.

Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Glycobiology (impact factor: 3.58). 08/2006; 16(7):641-50. DOI:10.1093/glycob/cwj103
Source: PubMed

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 into a GM3-deficient subclone of the 3LL Lewis lung carcinoma cell line (Uemura, S. (2003) Glycobiology, 13, 207-216). The GM3-reconstituted cells were resistant to apoptosis induced by etoposide and doxorubicin. There were no changes in the expression levels of topoisomerase IIalpha 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 serine-15-residue site 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 B-cell leukemia/lymphoma 2 (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 anticancer drug resistance through up-regulating the Bcl-2 protein in this lung cancer cell line.

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Keywords

3LL Lewis lung carcinoma cell line
 
anti-apoptotic protein B-cell leukemia/lymphoma 2
 
anticancer drug resistance
 
apoptosis induced
 
apoptotic signaling
 
Bcl-2 protein
 
cancer malignancy
 
cell proliferation
 
certain cell-cycle phases
 
DNA fragmentation
 
etoposide treatment
 
ganglioside GM3
 
ganglioside patterns
 
GM3 synthase
 
GM3-deficient subclone
 
GM3-reconstituted cells
 
lung cancer cell line
 
serine-15-residue site
 
topoisomerase IIalpha
 
wild-type 3LL Lewis lung carcinoma cells