Department of Neurosurgery, Westchester Medical Center, New York Medical College, Valhalla, NY, 10595, USA.
Department of Neurosurgery, Westchester Medical Center, New York Medical College, Valhalla, NY, 10595, USA.
Adv Biol Regul. 2022 Jan;83:100854. doi: 10.1016/j.jbior.2021.100854. Epub 2021 Dec 6.
Aberrant signaling of mechanistic target of rapamycin (mTOR aka mammalian target of rapamycin) is shown to be linked to tumorigenesis of numerous malignancies including glioblastoma (GB). mTOR is a serine threonine kinase that functions by forming two multiprotein complexes. These complexes are named mTORC1 and mTORC2 and activate downstream substrates that execute cellular and metabolic functions. This signaling cascade of PI3K/AKT/mTOR is often upregulated due to frequent loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 and mTORC2, which are composed of special binding partners. These complexes are sensitive to distinct stimuli. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. Since rapamycin and its analogue are less effective in treatment of GB, we used novel ATP-competitive dual inhibitors of mTORC1 and mTORC2, namely, Torin1, Torin2, and XL388. Torin2 caused a concentration dependent pharmacodynamic effects on inhibition of phosphorylation of the mTORC1 substrates S6K and 4E-BP1 as well as the mTORC2 substrate AKT resulting in suppression of tumor cell proliferation and migration. Torin1 showed similar effects only at higher doses. Another small molecule compound, XL388 suppressed cell proliferation at a higher dose but failed to inhibit cell migration. Torin1 suppressed phosphorylation of PRAS40, however, Torin2 completely abolished it. XL388 treatment inhibited the phosphorylation of PRAS40 at higher doses only. These findings underscore the use of novel compounds in treatment of cancer. In addition, formulation of third generation mTOR inhibitor "Rapalink-1" may provide new aspects to target mTOR pathways. Numerous inhibitors are currently being used in clinical trials that are aimed to target activated mTOR pathways.
已证实，机械靶标雷帕霉素（mTOR，又名哺乳动物雷帕霉素靶标）的异常信号与包括胶质母细胞瘤（GB）在内的多种恶性肿瘤的肿瘤发生有关。mTOR 是一种丝氨酸/苏氨酸激酶，通过形成两个多蛋白复合物发挥作用。这些复合物分别称为 mTORC1 和 mTORC2，并激活执行细胞和代谢功能的下游底物。PI3K/AKT/mTOR 信号通路通常因肿瘤抑制因子 PTEN 的频繁缺失而上调，PTEN 是一种与 PI3K 拮抗作用的磷酸酶。mTOR 通过形成两个多蛋白复合物 mTORC1 和 mTORC2 来调节细胞生长、运动和代谢，这两个复合物由特殊的结合伴侣组成。这些复合物对不同的刺激敏感。mTORC1 对营养物质敏感，mTORC2 通过 PI3K 和生长因子信号调节。由于雷帕霉素及其类似物在治疗 GB 方面效果较差，我们使用了新型 mTORC1 和 mTORC2 的 ATP 竞争性双重抑制剂，即 Torin1、Torin2 和 XL388。Torin2 对 mTORC1 底物 S6K 和 4E-BP1 以及 mTORC2 底物 AKT 的磷酸化抑制具有浓度依赖性的药效学作用，从而抑制肿瘤细胞的增殖和迁移。Torin1 仅在较高剂量下显示出类似的作用。另一种小分子化合物 XL388 在较高剂量下抑制细胞增殖，但不能抑制细胞迁移。Torin1 抑制 PRAS40 的磷酸化，而 Torin2 则完全消除了它。XL388 处理仅在较高剂量下抑制 PRAS40 的磷酸化。这些发现强调了新型化合物在癌症治疗中的应用。此外，第三代 mTOR 抑制剂“Rapalink-1”的制剂可能为靶向 mTOR 途径提供新的方面。目前有许多抑制剂正在临床试验中使用，旨在靶向激活的 mTOR 途径。
