Pedram Ali, Razandi Mahnaz, Wallace Douglas C, Levin Ellis R
Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, Long Beach, CA 90822, USA.
Mol Biol Cell. 2006 May;17(5):2125-37. doi: 10.1091/mbc.e05-11-1013. Epub 2006 Feb 22.
Steroid hormones have been reported to indirectly impact mitochondrial functions, attributed to nuclear receptor-induced production of proteins that localize in this cytoplasmic organelle. Here we show high-affinity estrogen receptors in the mitochondria of MCF-7 breast cancer cells and endothelial cells, compatible with classical estrogen receptors ERalpha and ERbeta. We report that in MCF-7, estrogen inhibits UV radiation-induced cytochrome C release, the decrease of the mitochondrial membrane potential, and apoptotic cell death. UV stimulated the formation of mitochondrial reactive oxygen species (mROS), and mROS were essential to inducing mitochondrial events of cell death. mROS mediated the UV activation of c-jun N-terminal kinase (JNK), and protein kinase C (PKC) delta, underlying the subsequent translocation of Bax to the mitochondria where oligomerization was promoted. E2 (estradiol) inhibited all these events, directly acting in mitochondria to inhibit mROS by rapidly up-regulating manganese superoxide dismutase activity. We implicate novel functions of ER in the mitochondria of breast cancer that lead to the survival of the tumor cells.
据报道，类固醇激素可间接影响线粒体功能，这归因于核受体诱导的定位于该细胞质细胞器中的蛋白质的产生。在这里，我们在MCF-7乳腺癌细胞和内皮细胞的线粒体中发现了高亲和力雌激素受体，与经典雌激素受体ERα和ERβ相符。我们报道，在MCF-7中，雌激素可抑制紫外线辐射诱导的细胞色素C释放、线粒体膜电位降低和凋亡细胞死亡。紫外线刺激了线粒体活性氧（mROS）的形成，而mROS对于诱导细胞死亡的线粒体事件至关重要。mROS介导了紫外线对c-jun氨基末端激酶（JNK）和蛋白激酶C（PKC）δ的激活，这是随后Bax转位至线粒体并促进其寡聚化的基础。雌二醇（E2）抑制了所有这些事件，通过快速上调锰超氧化物歧化酶活性直接作用于线粒体以抑制mROS。我们发现ER在乳腺癌线粒体中具有新功能，这些功能导致肿瘤细胞存活。
