Critical role of arachidonic acid-activated mTOR signaling in breast carcinogenesis and angiogenesis
Critical role of arachidonic acid-activated mTOR signaling in breast carcinogenesis and angiogenesis
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花生四烯酸激活的 mTOR 信号在乳腺癌发生和血管生成中的关键作用
DOI：
10.1038/onc.2012.47
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发表时间：
2013-01-10
期刊：
影响因子：
8
通讯作者：
Bai, X-C
中科院分区：
文献类型：
--
作者：
Wen, Z-H;Su, Y-C;Bai, X-C
哺乳动物雷帕霉素靶蛋白（mTOR）信号通路在许多癌症的发病机制中上调。花生四烯酸（AA）及其代谢产物在乳腺癌的发生发展中起重要作用，但AA促进乳腺肿瘤发生和发展的机制尚不清楚。我们发现AA和胞浆磷脂酶A2（cPLA 2）的水平与mTORC 1和mTORC 2的信号传导活性以及人乳腺肿瘤组织中血管上皮生长因子（VEGF）的表达水平密切相关。在培养的乳腺癌细胞中，AA有效地激活mTOR复合物1（mTORC 1）和mTORC 2。有趣的是，AA刺激的mTORC 1激活不依赖于氨基酸、磷脂酰肌醇3-激酶（PI 3-K）和结节性硬化症复合物2（TSC 2），这表明mTORC 1激活的新机制。进一步的研究表明，AA刺激mTORC 1活性，通过不稳定的mTOR-猛禽协会在ras同系物丰富的脑（Rheb）依赖性机制。此外，我们发现AA刺激的细胞增殖和血管生成需要mTOR活性，并且AA的作用是由脂氧合酶（LOX）而不是环氧合酶-2（考克斯-2）介导的。在动物模型中，雷帕霉素可抑制AA增强的大鼠乳腺肿瘤发生率、肿瘤重量和血管生成。我们的研究结果表明，AA是一种有效的细胞内刺激mTOR和AA激活的mTOR在血管生成和乳腺癌的肿瘤发生中起着关键作用。
The mammalian target of rapamycin (mTOR) signaling pathway is upregulated in the pathogenesis of many cancers. Arachidonic acid (AA) and its metabolites play critical role in the development of breast cancer, but the mechanisms through which AA promotes mammary tumorigenesis and progression are poorly understood. We found that the levels of AA and cytosolic phospholipase A2 (cPLA2) strongly correlated with the signaling activity of mTORC1 and mTORC2 as well as the expression levels of vascular epithelial growth factor (VEGF) in human breast tumor tissues. In cultured breast cancer cells, AA effectively activated both mTOR complex 1 (mTORC1) and mTORC2. Interestingly, AA-stimulated mTORC1 activation was independent of amino acids, phosphatidylinositol 3-kinase (PI3-K) and tuberous sclerosis complex 2 (TSC2), which suggests a novel mechanism for mTORC1 activation. Further studies revealed that AA stimulated mTORC1 activity through destabilization of mTOR–raptor association in ras homolog enriched in brain (Rheb)-dependent mechanism. Moreover, we showed that AA-stimulated cell proliferation and angiogenesis required mTOR activity and that the effect of AA was mediated by lipoxygenase (LOX) but not cyclooxygenase-2 (COX-2). In animal models, AA-enhanced incidences of rat mammary tumorigenesis, tumor weights and angiogenesis were inhibited by rapamycin. Our findings suggest that AA is an effective intracellular stimulus of mTOR and that AA-activated mTOR plays critical roles in angiogenesis and tumorigenesis of breast cancer.