Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer

被引:204
作者
Razandi, M
Pedram, A
Levin, ER
机构
[1] Long Beach Vet Hosp, Med Serv 111I, Dept Med, Long Beach, CA 90822 USA
[2] Univ Calif Irvine, Irvine, CA 92717 USA
关键词
D O I
10.1210/me.14.9.1434
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Chemotherapy or irradiation treatment induces breast cancer cell apoptosis, but this can be limited by estradiol (E-2) through unknown mechanisms. To investigate this, we subjected estrogen receptor-expressing human breast cancer cells (MCF-7 and ZR-75-1) to paclitaxel (taxol) or to UV irradiation. Marked increases in cell apoptosis were induced, but these were significantly reversed by incubation with E-2,. Taxol or UV stimulated c-Jun N-terminal kinase (JNK) activity, which was inhibited by E-2,. Expression of a dominant-negative Jnk-1 protein strongly prevented taxol- or UV-induced apoptosis, whereas E-2, inhibition of apoptosis was reversed by expression of constituitively active Jnk-1. As targets for participation in apoptosis, Bcl-2 and Bcl-xl were phosphorylated in response to JNK activation by taxol or UV; this was prevented by E-2,. Taxol or UV activated caspase activity in a JNK-dependent fashion and caused the cleavage of procaspase-9 to caspase-9, each inhibited by E-2,. Independently, the steroid also activated extracellular signal-regulated protein kinase activity, which contributed to the anti-apoptotic effects. We report novel and rapid mechanisms by which E-2, prevents chemotherapy or radiation-induced apoptosis of breast cancer, probably mediated through the plasma membrane estrogen receptor.
引用
收藏
页码:1434 / 1447
页数:14
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