Stathmin Regulates Hypoxia-Inducible Factor-1α Expression through the Mammalian Target of Rapamycin Pathway in Ovarian Clear Cell Adenocarcinoma.
Stathmin Regulates Hypoxia-Inducible Factor-1α Expression through the Mammalian Target of Rapamycin Pathway in Ovarian Clear Cell Adenocarcinoma.
复制标题
DOI：
10.1155/2013/279593
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Tachikawa E
中科院分区：
文献类型：
--
作者：
Tamura K;Yoshie M;Miyajima E;Kano M;Tachikawa E
Stathmin是一种微管不稳定的磷蛋白，在卵巢癌中高度表达，但这种蛋白在卵巢癌细胞中的病理生理意义仍然知之甚少。本研究报告了stathmin在卵巢透明细胞腺癌（CCA）缺氧时参与mTOR/HIF-1α/VEGF通路。在低氧条件下培养的CCA细胞系RMG-1中，HIF-1α蛋白和VEGF mRNA水平显著升高。mTOR复合物1的抑制剂雷帕霉素可降低HIF-1α的水平，阻断mTOR转录调节因子核糖体蛋白S6激酶1（S6 K）的磷酸化，表明缺氧激活CCA中mTOR/S6 K/HIF-1α信号转导。此外，stathmin敲低抑制缺氧诱导的HIF-1α和VEGF表达以及S6 K磷酸化。stathmin表达的沉默也减少了Akt磷酸化，这是mTOR/HIF-1α/VEGF信号通路中的关键事件。相反，stathmin过表达上调另一种CCA细胞系OVCAR-3细胞中缺氧诱导的HIF-1α和VEGF表达。此外，磷酸肌醇3-激酶（PI 3 K）抑制剂wortmannin抑制Akt活化，可降低HIF-1α和VEGF表达。这些结果表明，通过PI 3 K/Akt/mTOR途径调节HIF-1α在CCA中受stathmin控制。我们的发现指出了卵巢癌中stathmin调节的新机制。
Stathmin, a microtubule-destabilizing phosphoprotein, is highly expressed in ovarian cancer, but the pathophysiological significance of this protein in ovarian carcinoma cells remains poorly understood. This study reports the involvement of stathmin in the mTOR/HIF-1α/VEGF pathway in ovarian clear cell adenocarcinoma (CCA) during hypoxia. HIF-1α protein and VEGF mRNA levels were markedly elevated in RMG-1 cells, a CCA cell line, cultured under hypoxic conditions. Rapamycin, an inhibitor of mTOR complex 1, reduced the level of HIF-1α and blocked phosphorylation of ribosomal protein S6 kinase 1 (S6K), a transcriptional regulator of mTOR, demonstrating that hypoxia activates mTOR/S6K/HIF-1α signaling in CCA. Furthermore, stathmin knockdown inhibited hypoxia-induced HIF-1α and VEGF expression and S6K phosphorylation. The silencing of stathmin expression also reduced Akt phosphorylation, a critical event in the mTOR/HIF-1α/VEGF signaling pathway. By contrast, stathmin overexpression upregulated hypoxia-induced HIF-1α and VEGF expression in OVCAR-3 cells, another CCA cell line. In addition, suppression of Akt activation by wortmannin, a phosphoinositide 3-kinase (PI3K) inhibitor, decreased HIF-1α and VEGF expression. These results illustrate that regulation of HIF-1α through the PI3K/Akt/mTOR pathway is controlled by stathmin in CCA. Our findings point to a new mechanism of stathmin regulation during ovarian cancer.