Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.
Mol Cancer Ther. 2012 Jun;11(6):1342-52. doi: 10.1158/1535-7163.MCT-11-0723. Epub 2012 Apr 10.
mTOR is a serine/threonine kinase that acts by binding different sets of proteins forming two complexes, termed mTORC1 and mTORC2. mTOR is deregulated in a substantial proportion of ovarian tumors. Despite the use of drugs directed to mTOR in ongoing clinical trials, the functional relevance of the individual mTORC branches in ovarian cancer is not known. Here, we show that mTORC1 and mTORC2 were constitutively active in ovarian cancer cell lines. Knockdown of raptor or rictor, proteins required for the function of mTORC1 or mTORC2, respectively, resulted in profound inhibition of ovarian cancer cell proliferation. The knockdown of raptor had a more important inhibitory effect than the knockdown of rictor, indicating mTORC1 had a predominant role over mTORC2 in the control of ovarian cancer cell proliferation. Rapamycin decreased the proliferation of ovarian cancer cells, and this was accompanied by inhibition of the phosphorylation of S6, a protein used as readout of mTORC1 function. However, rapamycin had only a marginal effect on the phosphorylation status of 4E-BP1, another mTORC1 substrate. Therefore, mTORC1 probably controls p4E-BP1 along two distinct pathways, one of them sensitive to rapamycin and another insensitive. The dual PI3K/mTOR inhibitor BEZ235 was more efficient than rapamycin in its inhibitory action on ovarian cancer cell proliferation. Biochemically, BEZ235 completely inhibited pS6, p4E-BP1, and pAkt. Our results suggest that broad-spectrum mTOR inhibitors that block mTORC1 and mTORC2 are more desirable for their clinical development in ovarian cancer than agents exclusively targeting one of the mTOR branches.
mTOR 是一种丝氨酸/苏氨酸激酶，通过结合不同的蛋白质组形成两个复合物，分别称为 mTORC1 和 mTORC2。mTOR 在相当一部分卵巢肿瘤中失调。尽管在正在进行的临床试验中使用了针对 mTOR 的药物，但单个 mTORC 分支在卵巢癌中的功能相关性尚不清楚。在这里，我们表明 mTORC1 和 mTORC2 在卵巢癌细胞系中持续激活。敲低 raptor 或 rictor，分别是 mTORC1 或 mTORC2 功能所必需的蛋白质，导致卵巢癌细胞增殖受到深刻抑制。敲低 raptor 的抑制作用比敲低 rictor 更重要，表明 mTORC1 在控制卵巢癌细胞增殖方面比 mTORC2 更为重要。雷帕霉素降低了卵巢癌细胞的增殖，这伴随着 mTORC1 功能的读码蛋白 S6 磷酸化的抑制。然而，雷帕霉素对另一个 mTORC1 底物 4E-BP1 的磷酸化状态只有轻微影响。因此，mTORC1 可能通过两种不同的途径控制 p4E-BP1，其中一种途径对雷帕霉素敏感，另一种途径不敏感。双 PI3K/mTOR 抑制剂 BEZ235 在抑制卵巢癌细胞增殖方面比雷帕霉素更有效。从生化角度来看，BEZ235 完全抑制了 pS6、p4E-BP1 和 pAkt。我们的研究结果表明，与专门针对 mTOR 分支之一的药物相比，阻断 mTORC1 和 mTORC2 的广谱 mTOR 抑制剂在卵巢癌的临床开发中更具优势。
