Down-regulation of apoptosis-related bcl-2 but not bcl-xL or bax proteins in multidrug-resistant MCF-7/Adr human breast cancer cells
✍ Scribed by Besim Ogretmen; Ahmad R. Safa
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- French
- Weight
- 797 KB
- Volume
- 67
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Recent studies have shown that high levels of the apoptosisrelated proteins bcl-2 and bcl-x, increase, while over-expression of bcl-x, or bax decreases, resistance to drugs that induce apoptosis in some human cancer cells. In the present report, we investigated whether expression of these apoptosis-related proteins correlates with changes in the degree of resistance to apoptosis induced by doxorubucin, taxol, vincristine and VP-I6 and contributes to the development of acquired resistance in multidrug-resistant MCF-7IAdr breast cancer cells. In this study, high levels of bcl-x, and bax proteins are detected in both MCF-7 and MCF-7/Adr cells. In contrast, bcl-2 protein is down-regulated about 10-fold in MCF-7/Adr cells compared with MCF-7 cells. RT-PCR analysis showed that MCF-7/Adr cells express approximately 2-fold less bcl-2 mRNA than MCF-7 cells. Moreover, 4-24 hr cycloheximide treatment of MCF-7 and MCF-7/Adr cells did not affect the expression of bcl-2 protein, indicating that this protein is very stable in both cell lines. Our results suggest that bcl-2 expression is modulated partly by transcriptional, but mainly by post-transcriptional, mechanisms. Despite the down-regulation of bcl-2 in MCF-7/Adr cells and equal levels of bcl-x, and bax proteins in both cell lines, cytoplasmic DNA-histone complexes induced by doxorubucin, taxol, vincristine and VP-I 6 indicate that MCF-7/Adr cells are highly resistant to apoptosis. Moreover, treatments of MCF-7/ Adr cells with P-glycoprotein (P-gp) modulators. cyclosporin A and verapamil increased doxorubicin and vincristine-induced DNAfragmentation about I .4-and Z.S-fold, indicating that P-gp is involved in the development of resistance to chemotherapyinduced apoptosis in this cell line.