Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer.
Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer.
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DOI：
10.1158/1078-0432.ccr-09-1249
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发表时间：
2009-12-01
期刊：
影响因子：
--
通讯作者：
Evers BM
中科院分区：
文献类型：
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作者：
Gulhati P;Cai Q;Li J;Liu J;Rychahou PG;Qiu S;Lee EY;Silva SR;Bowen KA;Gao T;Evers BM
哺乳动物雷帕霉素靶蛋白（mTOR）激酶在PI 3 K/Akt下游起作用以调节细胞生长、代谢和细胞骨架。由于大约60%的散发性结直肠癌（CRC）表现出高水平的活化Akt，我们确定了下游mTOR信号通路组分是否在CRC中过表达和活化。利用HCT 116、KM 20、Caco-2和SW 480人CRC细胞来确定mTOR信号传导的药理学（使用雷帕霉素）或遗传学（使用RNAi）阻断对体内细胞增殖、凋亡、细胞周期进展和皮下生长的影响。我们表明mTOR复合物蛋白mTOR、Raptor和Rictor在CRC中过表达。用雷帕霉素治疗显著降低了一些CRC细胞系的增殖（雷帕霉素敏感），而其他细胞系对其作用具有抗性（雷帕霉素抗性）。瞬时siRNA介导的mTORC 2蛋白Rictor的敲低显著降低了雷帕霉素敏感和雷帕霉素耐药CRC细胞的增殖。稳定的shRNA介导的mTORC 1和mTORC 2的敲低降低了雷帕霉素敏感的CRC的增殖，增加了凋亡和减弱了细胞周期进程。此外，mTORC 1和mTORC 2的稳定敲除降低了增殖和衰减细胞周期进程，而只有mTORC 2敲除增加了雷帕霉素耐药CRC的凋亡。最后，mTORC 1和mTORC 2的敲除抑制了雷帕霉素敏感和耐药CRC在体内作为肿瘤异种移植物植入时的生长。靶向抑制mTORC 2蛋白，Rictor，导致生长抑制，并诱导雷帕霉素敏感和耐药CRC的细胞凋亡，这表明选择性靶向mTORC 2可能代表一种新的治疗策略，用于治疗CRC。
The mammalian target of rapamycin (mTOR) kinase acts downstream of PI3K/Akt to regulate cellular growth, metabolism and cytoskeleton. Since approximately 60% of sporadic colorectal cancers (CRCs) exhibit high levels of activated Akt, we determined whether downstream mTOR signaling pathway components are overexpressed and activated in CRCs. HCT116, KM20, Caco-2 and SW480 human CRC cells were utilized to determine the effects of pharmacological (using rapamycin) or genetic (using RNAi) blockade of mTOR signaling on cell proliferation, apoptosis, cell cycle progression and subcutaneous growth in vivo We show that the mTOR complex proteins, mTOR, Raptor and Rictor, are overexpressed in CRC. Treatment with rapamycin significantly decreased proliferation of some CRC cell lines (rapamycin-sensitive), while other cell lines were resistant to its effects (rapamycin-resistant). Transient siRNA-mediated knockdown of the mTORC2 protein, Rictor, significantly decreased proliferation of both rapamycin-sensitive and rapamycin-resistant CRC cells. Stable shRNA-mediated knockdown of both mTORC1 and mTORC2 decreased proliferation, increased apoptosis and attenuated cell cycle progression in rapamycin-sensitive CRCs. Moreover, stable knockdown of both mTORC1 and mTORC2 decreased proliferation and attenuated cell cycle progression, while only mTORC2 knockdown increased apoptosis in rapamycin-resistant CRCs. Finally, knockdown of both mTORC1 and mTORC2 inhibited growth of rapamycin-sensitive and -resistant CRCs in vivo when implanted as tumor xenografts. Targeted inhibition of the mTORC2 protein, Rictor, leads to growth inhibition and induces apoptosis in both rapamycin-sensitive and rapamycin-resistant CRCs, suggesting that selective targeting of mTORC2 may represent a novel therapeutic strategy for treatment of CRC.