Mammalian Target of Rapamycin (mTOR) Regulates Cellular Proliferation and Tumor Growth in Urothelial Carcinoma
Mammalian Target of Rapamycin (mTOR) Regulates Cellular Proliferation and Tumor Growth in Urothelial Carcinoma
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DOI：
10.2353/ajpath.2010.090872
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发表时间：
2010-06-01
影响因子：
6
通讯作者：
Eng, Charis
中科院分区：
文献类型：
--
作者：
Hansel, Donna E.;Platt, Eric;Eng, Charis
哺乳动物雷帕霉素靶点（mTOR）信号传导在许多癌症模型中与侵袭性肿瘤生长有关，尽管其在尿路上皮癌（UCC）中的作用尚未被广泛探索。磷酸化mTOR （P-mTOR）和下游靶标核糖体S6蛋白（P-S6）分别在74%（90/121）和55%（66/121）的肌肉侵袭性UCCs中表达。P- mtor强度和%阳性细胞与疾病特异性生存率降低相关（P = 0.04, P = 0.08）。此外，P-mTOR强度与病理分期增加相关（P < 0.01）， mTOR活性与体外细胞迁移有关。此外，通过雷帕霉素给予mTOR抑制，UCC细胞系RT4、T24、J82和UMUC3的细胞增殖以剂量依赖的方式降低至对照水平的6%，并且在J82、T24和RT4细胞中，1 nmol/L的mTOR抑制显著（P < 0.01,P < 0.01,P = 0.03），在UMUC3细胞中，10 nmol/L的mTOR抑制显著（P = 0.03）。Western blot结果显示，增殖降低与P-S6水平降低相对应，用mtor特异性siRNA预处理细胞可消除这种影响。TUNEL标记和PARP切割均未发现雷帕霉素对细胞凋亡的影响。雷帕霉素对t24异种移植小鼠的肿瘤体积减少55% (P = 0.03)，增殖减少40% （P < 0.01）。这些发现表明，mTOR通路激活经常发生在UCC中，mTOR抑制可能是减少UCC生长的潜在手段。（Am J Pathal 2010, 176:3062-3072; DOI: 10.2353/ajpath.2010.090872）
Mammalian target of rapamycin (mTOR) signaling has been associated with aggressive tumor growth in many cancer models, although its role in urothelial carcinoma (UCC) has not been extensively explored. Expression of phosphorylated mTOR (P-mTOR) and a downstream target, ribosomal S6 protein (P-S6), was identified in 74% (90/121) and 55% (66/121) of muscle-invasive UCCs, respectively. P-mTOR intensity and %positive cells were associated with reduced disease-specific survival (P = 0.04, P = 0.08, respectively). Moreover, P-mTOR intensity corresponded to increased pathological stage (P < 0.01), and mTOR activity was associated with cell migration in vitro. In addition, mTOR inhibition via rapamycin administration reduced cell proliferation in UCC cell lines RT4, T24, J82, and UMUC3 in a dose-dependent manner to 6% of control levels and was significant at 1 nmol/L in J82, T24, and RT4 cells (P < 0.01,P < 0.01,P = 0.03, respectively) and at 10 nmol/L in UMUC3 cells (P = 0.03). Reduced proliferation corresponded with reduced P-S6 levels by Western blot, and effects were ablated by pretreatment of cells with mTOR-specific siRNA. No effects of rapamycin on apoptosis were identified by TUNEL labeling or PARP cleavage. Administration of rapamycin to T24-xenografted mice resulted in a 55% reduction in tumor volume (P = 0.03) and a 40% reduction in proliferation (P < 0.01) compared with vehicle-injected mice. These findings indicate that mTOR pathway activation frequently occurs in UCC and that mTOR inhibition may be a potential means to reduce UCC growth. (Am J Pathal 2010, 176:3062-3072; DOI: 10.2353/ajpath.2010.090872)