Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer
Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer
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DOI：
10.1210/me.14.9.1434
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发表时间：
2000-09-01
影响因子：
--
通讯作者：
Levin, ER
中科院分区：
文献类型：
--
作者：
Razandi, M;Pedram, A;Levin, ER
化疗或放射治疗诱导乳腺癌细胞凋亡，但这可以通过未知的机制受到雌二醇（E-2）的限制。为了研究这一点，我们对表达雌激素受体的人乳腺癌细胞（MCF-7和ZR-75-1）进行紫杉醇（紫杉醇）或紫外线照射。细胞凋亡的显着增加，诱导，但这些被显着逆转与E-2孵育，。紫杉醇或紫外线刺激c-Jun N-末端激酶（JNK）活性，而E-2、.显性负性JNK-1蛋白的表达强烈阻止紫杉醇或UV诱导的细胞凋亡，而E-2，细胞凋亡的抑制被逆转的表达constitutional活性JNK-1。作为参与细胞凋亡的靶标，Bcl-2和Bcl-xl响应于紫杉醇或UV的JNK活化而磷酸化;这被E-2阻止。紫杉醇或紫外线以JNK依赖的方式激活caspase活性，并导致caspase-9前体裂解为caspase-9，每一种都被E-2抑制。独立地，类固醇还激活细胞外信号调节蛋白激酶活性，这有助于抗凋亡作用。我们报告了新的和快速的机制，其中E-2，防止化疗或放射诱导的乳腺癌细胞凋亡，可能通过质膜雌激素受体介导。
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.