Jhanwar-Uniyal Meena, Wainwright John V, Mohan Avinash L, Tobias Michael E, Murali Raj, Gandhi Chirag D, Schmidt Meic H
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. 2019 May;72:51-62. doi: 10.1016/j.jbior.2019.03.003. Epub 2019 Apr 11.
Activation of Mechanistic target of rapamycin (mTOR) signaling plays a crucial role in tumorigenesis of numerous malignancies including glioblastoma (GB). The Canonical PI3K/Akt/mTOR signaling cascade is commonly upregulated due to loss of the tumor suppressorm PTEN, a phosphatase that acts antagonistically to the kinase (PI3K) in conversion of PIP2 to PIP3. mTOR forms two multiprotein complexes, mTORC1 and mTORC2 which are composed of discrete protein binding partners to regulate cell growth, motility, and metabolism. These complexes are sensitive to distinct stimuli, as mTORC1 is sensitive to nutrients while mTORC2 is regulated via PI3K and growth factor signaling. The main function of mTORC1 is to regulate protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. On the other hand, mTORC2 is responsive to growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases like Akt and SGK and it also plays a crucial role in maintenance of normal and cancer cells through its association with ribosomes, and is involved in cellular metabolic regulation. mTORC1 and mTORC2 regulate each other, as shown by the fact that Akt regulates PRAS40 phosphorylation, which disinhibits mTORC1 activity, while S6K regulates Sin1 to modulate mTORC2 activity. Allosteric inhibitors of mTOR, rapamycin and rapalogs, remained ineffective in clinical trials of Glioblastoma (GB) patients, in part due to their incomplete inhibition of mTORC1 as well as unexpected activation of mTOR via the loss of negative feedback loops. In recent years, novel ATP binding inhibitors of mTORC1 and mTORC2 suppress mTORC1 activity completely by total dephosphorylation of its downstream substrate pS6K, while effectively suppressing mTORC2 activity, as demonstrated by complete dephosphorylation of pAKT. Furthermore by these novel combined mTORC1/mTORC2 inhibitors reduced the proliferation and self-renewal of GB cancer stem cells. However, a search of more effective way to target mTOR has generated a third generation inhibitor of mTOR, "Rapalink", that bivalently combines rapamycin with an ATP-binding inhibitor, which effectively abolishes the mTORC1 activity. All in all, the effectiveness of inhibitors of mTOR complexes can be judged by their ability to suppress both mTORC1/mTORC2 and their ability to impede both cell proliferation and migration along with aberrant metabolic pathways.
雷帕霉素作用机制靶点（mTOR）信号通路的激活在包括胶质母细胞瘤（GB）在内的多种恶性肿瘤的发生发展中起着关键作用。由于肿瘤抑制因子PTEN的缺失，经典的PI3K/Akt/mTOR信号级联通常会上调，PTEN是一种磷酸酶，在PIP2转化为PIP3的过程中与激酶（PI3K）起拮抗作用。mTOR形成两种多蛋白复合物，mTORC1和mTORC2，它们由不同的蛋白结合伙伴组成，以调节细胞生长、运动和代谢。这些复合物对不同的刺激敏感，因为mTORC1对营养物质敏感，而mTORC2通过PI3K和生长因子信号通路调节。mTORC1的主要功能是通过下游分子4E-BP1（也称为EIF4E-BP1）和S6K来调节蛋白质合成和细胞生长。另一方面，mTORC2通过磷酸化一些AGC激酶（如Akt和SGK）的C末端疏水基序来响应生长因子信号，并且它通过与核糖体的结合在维持正常细胞和癌细胞中也起着关键作用，还参与细胞代谢调节。mTORC1和mTORC2相互调节，如Akt调节PRAS40磷酸化，从而解除对mTORC1活性的抑制，而S6K调节Sin1以调节mTORC2活性。mTOR的变构抑制剂雷帕霉素及其类似物在胶质母细胞瘤（GB）患者的临床试验中仍然无效，部分原因是它们对mTORC1的抑制不完全以及由于负反馈回路的丧失导致mTOR意外激活。近年来，新型的mTORC1和mTORC2的ATP结合抑制剂通过完全去磷酸化其下游底物pS6K来完全抑制mTORC1活性，同时有效地抑制mTORC2活性，这通过pAKT的完全去磷酸化得到证明。此外，这些新型的mTORC1/mTORC2联合抑制剂降低了GB癌症干细胞的增殖和自我更新能力。然而，寻找更有效的靶向mTOR的方法产生了第三代mTOR抑制剂“Rapalink”，它将雷帕霉素与一种ATP结合抑制剂二价结合，可以有效消除mTORC1活性。总而言之，mTOR复合物抑制剂的有效性可以通过它们抑制mTORC1/mTORC2的能力以及它们阻碍细胞增殖、迁移和异常代谢途径的能力来判断。
