Expression of an activated mammalian target of rapamycin in adenocarcinoma of the cervix: A potential biomarker and molecular target therapy
Expression of an activated mammalian target of rapamycin in adenocarcinoma of the cervix: A potential biomarker and molecular target therapy
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DOI：
10.1002/mc.20402
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发表时间：
2008-06-01
影响因子：
4.6
通讯作者：
Minegishil, Takashi
中科院分区：
文献类型：
--
作者：
Faried, Leri S.;Faried, Ahmad;Minegishil, Takashi
Akt/mTOR通路的改变已经在许多类型的癌症中观察到，因此该通路代表了分子治疗的令人兴奋的新靶点。我们研究了宫颈腺癌患者激活的Akt（p-Akt）和mTOR（p-mTOR）的表达，以及p-Akt/p-mTOR通路对抑制剂雷帕霉素和LY 294002联合常规治疗顺铂的体外反应。对26例宫颈腺癌患者进行p-Akt和p-mTOR免疫组化分析。蛋白质印迹分析用于确定宫颈癌细胞系中参与对化疗的响应的蛋白质表达。结果表明，p-Akt和p-mTOR在宫颈腺癌中的阳性率分别为50%和53.8%。p-mTOR表达是判断预后的独立指标。观察到p-Akt和p-mTOR之间显著相关。它们的表达与临床病理因素无关。在体外研究中，CP 150的顺铂通过激活半胱天冬酶级联，抑制Akt、mTOR、p70 S6 K和4 EBP 1，靶向细胞凋亡和存活途径。雷帕霉素与顺铂的组合诱导协同相互作用。另一方面，与LY 294002组合产生协同或拮抗作用，这取决于所给予的剂量。雷帕霉素预处理增强顺铂诱导的凋亡细胞死亡，并增强对存活途径的阻断。总体而言，p-mTOR的表达是宫颈腺癌的重要预后标志物，也是治疗宫颈癌的潜在分子靶点。mTOR通路的抑制有助于宫颈癌细胞系中顺铂诱导的细胞凋亡。(C)2007 Wiley-Liss，Inc.
Alterations of the Akt/mTOR pathway have been observed in numerous types of cancer, thus this pathway represents an exciting new target for molecular therapeutics. We investigated the expression of activated Akt (p-Akt) and mTOR (p-mTOR) in patients with adenocarcinoma of the cervix and the involvement of the p-Akt/p-mTOR pathway in response to combination of inhibitor agents, rapamycin and LY294002, with conventional therapy, cisplatin, in vitro. Immunohistochemistry analysis of p-Akt and p-mTOR was conducted in 26 patients with adenocarcinoma of the cervix. Western blot analysis was performed to determine the protein expression involved in response to chemotherapy in cervical cancer cell lines. The results showed that p-Akt and p-mTOR were identified in 50% and 53.8% of adenocarcinoma of the cervix. The expression of p-mTOR was a significant independent marker for prognosis. A significant correlation between p-Akt and p-mTOR was observed. There was no correlation between their expressions with any of clinicopathological factors. In the in vitro study, cisplatin at CP150 targets both the apoptosis and survival pathway by activating the caspase-cascade; inhibiting Akt, mTOR, p70S6K, and 4EBP1. Combination of rapamycin with cisplatin induced synergistic interaction. On the other hand, combination with LY294002 resulted in either synergistic or antagonistic effect depending on the doses given. Rapamycin pretreatment potentiated cisplatin-induced apoptosis cell death and enhanced blocking of the survival pathway. Overall, the expression of p-mTOR is a significant prognostic marker of adenocarcinoma of the cervix and a potential molecular target for the treatment of cervical cancer. Inhibition of the mTOR pathway contributes to cisplatin-induced apoptosis in cervical cancer cell lines. (C) 2007 Wiley-Liss, Inc.