Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax
Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax
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DOI：
10.1016/j.bcp.2011.11.027
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发表时间：
2012-02-15
影响因子：
5.8
通讯作者：
Perez-Tomas, R.
中科院分区：
文献类型：
--
作者：
Espona-Fiedler, M.;Soto-Cerrato, V.;Perez-Tomas, R.
Pl3K/AKT/mTOR信号通路调控细胞的增殖、存活和血管生成。雷帕霉素的哺乳动物靶标(MTOR)是一种在细胞内普遍表达的蛋白激酶，通过整合营养和激素信号来调节细胞的生长和存活。MTOR存在于mTORC1和mTORC2两个复合体中。MTOR蛋白的过度激活与癌症的发生有关，使mTOR成为癌症治疗的一个有吸引力的靶点。前列环素(PG)和前列环素(OBX)是催乳素家族的两个成员，是目前正在进行临床试验的具有抗癌特性的小分子。在这篇论文中，我们证明了mTOR是黑色素瘤(一种高度耐药的癌症模型)中两种前列腺素的分子靶点。PG或OBX抑制mTORC1和mTORC2复合体导致S473处AICT磷酸化丧失，阻止其完全激活，而对T308无明显影响。PG对mTORC2的抑制作用最强(89%)。使用表面等离子体共振(SPR)的结合分析提供了这些小分子与mTOR相互作用的动力学和亲和力数据。此外，在硅胶建模中，产生了结合模式的详细原子描述。这些结果为理解这些分子的作用机制提供了新的数据，并提供了新的结构数据，将允许开发更具特异性的mTOR抑制剂用于癌症治疗。(C)2011 Elsevier Inc.保留所有权利。
The Pl3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis. The mammalian target of rapamycin (mTOR) is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mTORC2. Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AICT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modeling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment. (C) 2011 Elsevier Inc. All rights reserved.