Estrogen suppresses MLK3-mediated apoptosis sensitivity in ER+ breast cancer cells.
Estrogen suppresses MLK3-mediated apoptosis sensitivity in ER+ breast cancer cells.
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DOI：
10.1158/0008-5472.can-09-3492
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发表时间：
2010-02-15
期刊：
影响因子：
11.2
通讯作者：
Rana A
中科院分区：
文献类型：
--
作者：
Rangasamy V;Mishra R;Mehrotra S;Sondarva G;Ray RS;Rao A;Chatterjee M;Rana B;Rana A
Estrogen stimulates growth and inhibits apoptosis of breast cancer cells via genomic and non-genomic actions. However, the detailed mechanism by which estrogen inhibits the pro-apoptotic pathways that might impede the normal homeostasis and action of chemotherapeutic drugs in breast cancer cells is not well understood. Here, we report a negative regulation of a pro-apoptotic kinase, Mixed Lineage Kinase 3 (MLK3) by 17β-estradiol (E2) that hinders cytotoxic drug-induced cell death in estrogen receptor positive (ER+) breast cancer cells. MLK3 kinase activities were significantly higher in estrogen receptor negative (ER−), progesterone receptor negative (PR−) primary human breast tumors, suggesting that E2 might have a negative role in regulating MLK3 kinase activity. The kinase activities of MLK3 and its downstream target, JNK were rapidly inhibited by E2 in ER+ but not in ER− breast cancer cells. The inhibition of MLK3 kinase activity by E2 was mediated via activation of protein kinase B (PKB/AKT) because specific knockdown of AKT1/2 prevented the E2-induced inhibition of MLK3. Furthermore, E2-induced inhibition of MLK3 kinase activity involved a direct phosphorylation of MLK3 at Ser 674 site by AKT, which resulted in an attenuation of the pro-apoptotic function of MLK3. In addition, a pan-MLK inhibitor (CEP-11004) significantly attenuated Taxol-induced cell death, which was further synergized by E2. Thus, our data suggest that E2 negatively regulates the pro-apoptotic function of MLK3 during breast cancer pathogenesis and therefore MLK3 and other MLK family members might play an important role in cytotoxic drug-induced cell death in ER+ breast cancer cells.
