Down-regulation of apoptosis-related bcl-2 but not bcl-x(L) or bax proteins in multidrug-resistant MCF-7/Adr human breast cancer cells

Besim Ogretmen, Ahmad R. Safa

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Recent studies have shown that high levels of the apoptosis-related proteins bcl-2 and bcl-x(L) increase, while over-expression of bcl-x(s) 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-16 and contributes to the development of acquired resistance in multidrug-resistant MCF-7/Adr breast cancer cells. In this study, high levels of bcl-x(L) 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(L) and bax proteins in both cell lines, cytoplasmic DNA-histone complexes induced by doxorubucin, taxol, vincristine and VP-16 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 DNA fragmentation about 1.4- and 2.5-fold, indicating that P-gp is involved in the development of resistance to chemotherapy-induced apoptosis in this cell line.

Original languageEnglish (US)
Pages (from-to)608-614
Number of pages7
JournalInternational Journal of Cancer
Volume67
Issue number5
DOIs
StatePublished - Sep 23 1996

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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