Section 16
Chapter 15,121

Bcl-2 overexpression sensitizes MCF-7 cells to genistein by multiple mechanisms

Tophkhane, C.; Yang, S.; Bales, W.; Archer, L.; Osunkoya, A.; Thor, A.D.; Yang, X.

International Journal of Oncology 31(4): 867-874


ISSN/ISBN: 1019-6439
PMID: 17786319
DOI: 10.3892/ijo.31.4.867
Accession: 015120696

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Genistein is a soy isoflavone with anti-tumor properties. Genistein-induced apoptosis involves Bcl-2 down-regulation. However, overexpression of Bcl-2 in breast cancer has been associated with better prognosis and response to hormonal therapy. To examine genistein's effect on breast cancer cells with different Bcl-2 levels, we established control (MCF-7/PV) and Bcl-2 overexpressing MCF-7 (MCF-7/Bcl-2) cell lines and characterized genistein regulated apoptosis and cell cycle progression in these cells. Our results demonstrate that overexpression of Bcl-2 rendered MCF-7 cells more sensitive, rather than resistant, to genistein. We found that genistein induces enhanced cytochrome c release and mitochondrial membrane depolarization in MCF-7/Bcl-2 cells, as compared to control. We also found that genistein increases Bcl-2 levels and Bcl-2/Bax ratio in the mitochondrial fractions of MCF-7/Bcl-2 cells, suggesting that disturbed Bcl-2/Bax distribution may cause cytochrome c release and apoptosis in these cells. Cell cycle analysis indicated that genistein induces G0/G1 arrest in MCF-7/PV cells but increases in G2/M arrest in MCF-7/Bcl-2 cells. This was accompanied by modified responses of several cell cycle regulators, such as p21 and cyclin B I. Taken together, our results indicate that genistein-Bcl-2 interaction switches Bcl-2 from an antiapoptotic protein into a proapoptotic protein, which involves disturbed Bcl-2/Bax distribution in mitochondria, increased cytochrome c release and modified cell cycle regulation.

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