mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways.
mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways.
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DOI：
10.1158/0008-5472.can-10-4058
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发表时间：
2011-05-01
期刊：
影响因子：
11.2
通讯作者：
Evers BM
中科院分区：
文献类型：
--
作者：
Gulhati P;Bowen KA;Liu J;Stevens PD;Rychahou PG;Chen M;Lee EY;Weiss HL;O'Connor KL;Gao T;Evers BM
磷脂酰肌醇3 - 激酶（PI3K）/Akt信号通路的激活与结直肠癌（CRC）的生长和进展有关。我们先前已表明，雷帕霉素靶蛋白（mTOR）激酶作为PI3K/Akt信号通路的下游效应因子，调控着CRC的肿瘤发生。然而，mTOR及其相互作用伙伴在调控CRC进展和转移方面的作用仍知之甚少。我们发现，随着CRC分期的进展，mTOR、Raptor和Rictor的mRNA表达增加，这表明mTOR信号通路可能与CRC进展和转移有关。与正常结肠相比，原发性CRC（IV期）及其匹配的远处转移灶中mTOR、Raptor和Rictor蛋白水平也显著升高。使用雷帕霉素或对mTORC1（Raptor）和mTORC2（Rictor）进行稳定抑制来阻断mTOR信号通路，可减弱CRC的迁移和侵袭能力。此外，敲低mTORC1和mTORC2可诱导间充质 - 上皮转化，并增强CRC对奥沙利铂的化疗敏感性。我们观察到，在同时抑制mTORC1和mTORC2时，细胞间接触增加，肌动蛋白细胞骨架重塑减少，同时小GTP酶RhoA和Rac1的活化降低。最后，无论定植部位如何，靶向抑制mTORC1和mTORC2可完全消除CRC在体内的转移。我们的研究结果支持mTORC1和mTORC2活性升高通过RhoA和Rac1信号通路在调控CRC的上皮 - 间质转化、运动性和转移方面发挥作用。这些发现为将抑制mTORC1和mTORC2的mTOR激酶抑制剂纳入CRC患者的治疗方案提供了理论依据。
Activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling is associated with growth and progression of colorectal cancer (CRC). We have previously shown that the mammalian target of rapamycin (mTOR) kinase, a downstream effector of PI3K/Akt signaling, regulates tumorigenesis of CRC. However, the contribution of mTOR and its interaction partners towards regulating CRC progression and metastasis remains poorly understood. We found that increased expression of mTOR, Raptor and Rictor mRNA was noted with advanced stages of CRC suggesting that mTOR signaling may be associated with CRC progression and metastasis. mTOR, Raptor and Rictor protein levels were also significantly elevated in primary CRCs (stage IV) and their matched distant metastasis compared to normal colon. Inhibition of mTOR signaling, using rapamycin or stable inhibition of mTORC1 (Raptor) and mTORC2 (Rictor), attenuated migration and invasion of CRCs. Furthermore, knockdown of mTORC1 and mTORC2 induced a mesenchymal-epithelial transition and enhanced chemosensitivity of CRCs to oxaliplatin. We observed increased cell-cell contact as well as decreased actin cytoskeletal remodeling concomitant with decreased activation of the small GTPases, RhoA and Rac1, upon inhibition of both mTORC1 and mTORC2. Finally, establishment of CRC metastasis in vivo was completely abolished with targeted inhibition of mTORC1 and mTORC2 irrespective of the site of colonization. Our findings support a role for elevated mTORC1 and mTORC2 activity in regulating EMT, motility and metastasis of CRCs via RhoA and Rac1 signaling. These findings provide the rationale for including mTOR kinase inhibitors, which inhibit both mTORC1 and mTORC2, as part of the therapeutic regimen for CRC patients.