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

被引:12
作者
Tophkhane, Chaitali
Yang, Shihe
Bales, Wesley
Archer, Linda
Osunkoya, Adeboye
Thor, Ann D.
Yang, Xiaohe [1 ]
机构
[1] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73104 USA
[2] Vet Affairs Med Ctr, Oklahoma City, OK 73104 USA
[3] Univ Colorado, Hlth Sci Ctr, Dept Pathol, Aurora, CO 80045 USA
关键词
genistein; Bcl-2; apoptosis; mitochondria; cell cycle;
D O I
暂无
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:867 / 874
页数:8
相关论文
共 56 条
[1]  
AKIYAMA T, 1987, J BIOL CHEM, V262, P5592
[2]  
Akiyama T., 1991, METHOD ENZYMOL, V201, P362
[3]   Bcl-2 overexpression results in reciprocal downregulation of Bcl-XL and sensitizes human testicular germ cell tumours to chemotherapy-induced apoptosis [J].
Arriola, EL ;
Rodriguez-Lopez, AM ;
Hickman, JA ;
Chresta, CM .
ONCOGENE, 1999, 18 (07) :1457-1464
[4]  
BERNARDI P, 1992, J BIOL CHEM, V267, P2934
[5]  
Bossy-Wetzel E, 2000, METHOD ENZYMOL, V322, P235
[6]   Conversion of Bcl-2 to a Bax-like death effector by caspases [J].
Cheng, EHY ;
Kirsch, DG ;
Clem, RJ ;
Ravi, R ;
Kastan, MB ;
Bedi, A ;
Ueno, K ;
Hardwick, JM .
SCIENCE, 1997, 278 (5345) :1966-1968
[7]  
Choi YH, 1998, INT J ONCOL, V13, P391
[8]   Genistein inactivates bcl-2, delays the G2/M phase of the cell cycle, and induces apoptosis of human breast adenocarcinoma MCF-7 cells [J].
Constantinou, AI ;
Kamath, N ;
Murley, JS .
EUROPEAN JOURNAL OF CANCER, 1998, 34 (12) :1927-1934
[9]   The Bcl-2 family: roles in cell survival and oncogenesis [J].
Cory, S ;
Huang, DCS ;
Adams, JM .
ONCOGENE, 2003, 22 (53) :8590-8607
[10]   Killing cancer cells by flipping the Bcl-2/Bax switch [J].
Cory, S ;
Adams, JM .
CANCER CELL, 2005, 8 (01) :5-6