摘要
雷帕霉素(雷帕霉素靶蛋白)的进化守恒的机械目标形式两个功能不同的复合物——mTORC1和 mTORC2。 mTORC1由雷帕霉素靶蛋白(mTOR), raptor和mLST8(GβL)组成。mTORC1对雷帕霉素敏感, 被认为通过养分供应和生长因子,控制自主细胞生长。 mTORC2包含核心组件雷帕霉素靶蛋白(mTOR)、mLST8 、Rictor、mSIN1和Protor1/2,其对雷帕霉素极不敏感。 mTORC2 特异性检测生长因子和调节细胞增殖、代谢、肌动蛋白重排和生存。mTOR信号的失调经常发生在多种人类恶性疾病,使其成为一个癌症治疗的关键和验证的目标。然而,雷帕霉素作为单一试剂治疗的效力被抑制,部分地被许多强有力的mTORC1依赖性负反馈环路所抑制。虽然同时定位的mTORC1和mTORC2的ATP竞争性mTOR抑制剂的临床前和临床研究在癌症治疗上已经显示比rapalogs更大的效用,但是PI3- K / PDK1和Akt(Thr308)的mTORC1抑制诱导负反馈活化可能足以促进细胞的存活。最近的癌症生物学研究表明,mTORC2的是一个机具发展前途的靶标,因为它的活动对许多癌症的发展至关重要。这些研究提供了开发抑制剂特异性靶向mTORC2的基本原理。mTORC2不扰乱mTORC1-依赖负反馈环路,并具有更可接受的治疗窗。本文总结了目前对mTORC2的信号和功能的理解,特别是致使肿瘤的功能,突出了在癌症治疗中靶向mTORC2的现状和未来前景。
关键词: 癌症、mSIN1、 mTORC2、 mTOR、雷帕霉素、rictor。
Current Cancer Drug Targets
Title:Targeted Inhibition of Rictor/mTORC2 in Cancer Treatment: A New Era after Rapamycin
Volume: 16 Issue: 4
Author(s): Zhipeng Zou, Juan Chen, Jun Yang, Xiaochun Bai
Affiliation:
关键词: 癌症、mSIN1、 mTORC2、 mTOR、雷帕霉素、rictor。
摘要: The evolutionarily conserved mechanistic target of rapamycin (mTOR) forms two functionally distinct complexes, mTORC1 and mTORC2. mTORC1, consisting of mTOR, raptor, and mLST8 (GβL), is sensitive to rapamycin and thought to control autonomous cell growth in response to nutrient availability and growth factors. mTORC2, containing the core components mTOR, mLST8, Rictor, mSIN1, and Protor1/2 is largely insensitive to rapamycin. mTORC2 specifically senses growth factors and regulates cell proliferation, metabolism, actin rearrangement, and survival. Dysregulation of mTOR signaling often occurs in a variety of human malignant diseases, rendering it a crucial and validated target in cancer treatment. However, the effectiveness of rapamycin as single-agent therapy is suppressed, in part, by the numerous strong mTORC1-dependent negative feedback loops. Although preclinical and clinical studies of ATP-competitive mTOR inhibitors that target both mTORC1 and mTORC2 have shown greater effectiveness than rapalogs for cancer treatment, the mTORC1 inhibition-induced negative feedback activation of PI3- K/PDK1 and Akt (Thr308) may be sufficient to promote cell survival. Recent cancer biology studies indicated that mTORC2 is a promising target, since its activity is essential for the development of a number of cancers. These studies provide a rationale for developing inhibitors specifically targeting mTORC2, which do not perturb the mTORC1- dependent negative feedback loops and have a more acceptable therapeutic window. This review summarizes the present understanding of mTORC2 signaling and functions, especially tumorigenic functions, highlighting the current status and future perspectives for targeting mTORC2 in cancer treatment.
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Zhipeng Zou, Juan Chen, Jun Yang, Xiaochun Bai , Targeted Inhibition of Rictor/mTORC2 in Cancer Treatment: A New Era after Rapamycin, Current Cancer Drug Targets 2016; 16 (4) . https://dx.doi.org/10.2174/1568009616666151113120830
DOI https://dx.doi.org/10.2174/1568009616666151113120830 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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