摘要
哺乳动物雷帕霉素靶(mTOR)和蛋白激酶B(Akt/PKB)与肿瘤发生的密切关系已被广泛地认可.mTOR是一种丝/苏氨酸激酶,可以通过影响mRNA转录、代谢、自噬等方式调控细胞的生长.它既是PI3K的效应分子,也可以是PI3K的反馈调控因子.mTORC1和mTORC2是mTOR的两种不同复合物.对雷帕霉素敏感的mTORC1受到营养、生长因子、能量和应激4种因素的影响.生长因子通过PI3K/Akt信号通路调控mTORC1是最具特征性调节路径.而mTORC2最为人熟知的是作为Akt473磷酸化位点的上游激酶.同样,Akt/PKB在细胞增殖分化、迁移生长过程中发挥着重要作用.随着Thr308和Ser473两个位点激活,Akt/PKB也得以全面活化.因此,mTORC2-AktmTORC1的信号通路在肿瘤形成和生长中是可以存在的.目前临床肿瘤治疗中,PI3K/Akt/mTOR是重要的靶向治疗信号通路.然而,仅抑制mTORC1活性,不是所有的肿瘤都能得到预期控制.雷帕霉素虽然能抑制mTORC1,但也能反馈性地增加PI3K信号活跃度,从而影响治疗预后.近来发现的第二代抑制剂可以同时抑制mTORC1/2和PI3K活性,这种抑制剂被认为在肿瘤治疗上颇具前景.本综述着重阐述了PI3K/Akt/mTOR信号通路的传导、各因子之间的相互调控以及相关抑制剂的发展.
The mammalian target of rapamycin （mTOR） and Akt/PKB （protein kinase B） are closely related to cancers. As a downstream effector and regulator of PI3K, the roTOR molecule regulates mRNA translation, metabolism and autophagy to affect cell growth. There are two types of mTOR multi protein complexes： mTORC1 and mTORC2. The former is sensitive to rapamycin and acts to respond to four major regulatory stimulations of nutrients, growth factors, energy and stress. The growth factor/PI3K/Akt pathway is the most identified signaling pathway for which to regulate. The latter is characterized as a kinase to phosphorylate Akt at Ser473, and then regulate cell growth/proliferatlon, motility, survival, and differentiation, especially when coordinated with Thr308 of Akt. The PI3K/Akt/mTOR pathway is an important therapeutic target of cancer treatments for its critical role in cancer cells. However, the first generation mTORCl-specific inhibitors of rapamycin analogs showed limited efficacy, probably due to the feedback activation of upstream PI3K signaling. Recently, the second generation inhibitors acted on both of mTORC1/2 and PI3K, which can be more promising in cancer treatment. This review describes recent reports on such novel inhibitors and their functions in the PI3K/Akt/mTOR signaling pathway.
出处
《中国生物化学与分子生物学报》
CAS
CSCD
北大核心
2014年第10期949-956,共8页
Chinese Journal of Biochemistry and Molecular Biology
基金
国家自然科学基金(No.81070489,No.81270654)资助项目~~
