IGF-1信号通路在细胞衰老与肿瘤形成过程中的作用与分子机制研究

Cancer is the leading cause of human mortality worldwide.Uncontrolled cell proliferation and evasion of apoptosis are hallmarks of all cancers. As a basic biological process, cellular senescence is intertwined with cell proliferation.In general, cellular senescence, which leads to irreversible growth arrest even in the presence of growth factors, can be categorized into replicative senescence caused by telomere shortening, and premature senescence caused by variety of cellular stress signals including oncogenic stress. The importance of cellular senescence is increasingly being recognized because it is prevalent in pre-malignant tumors. Given the tumor-suppressing potential of cellular senescence, it is of high interest in developing new strategies of senescence-inducing interventions for cancer treatment. Insulin-like growth factor I (IGF-1) signaling is well recognized for its role in enhancing proliferation and survival. Numerous studies have demonstrated that elevated IGF-1 signaling is closely related to tumorigenesis in animal models as well as in humans. Paradoxically, dampened IGF-1 signaling is associated with increased longevity in various model organisms. Previous studies and work-in-progress from our lab show that acute IGF-1 treatment promotes cell proliferation and survival. In sharp contrast, prolonged IGF-1 treatment leads to SIRT1- and p53-dependent premature cell senescence. We demonstrate that IGF-1 represses the deacetylase activity of SIRT1, leading to increased p53 protein acetylation and transcriptional activity. Thus, it seems that IGF-1 possesses dual function in promoting cell proliferation and in inducing premature cellular senescence, the molecular mechanisms of which, however, remain elusive. Here, we hypothesize that p53 serves as a molecular switch in modulating IGF-1 dual function. This application aims to dissect the molecular mechanisms with which IGF-1 down-regulates SIRT1 activity, to investigate the importance of IGF-1-SIRT1-p53 axis in cell senescence and tumorigenesis in vivo, and to explore its implications in human tumorigenesis. This study will not only offer new insights on cell proliferation and senescence, but also help identifying novel therapeutical targets for cancer treatment.

癌症是异常细胞增殖和凋亡导致的恶性疾病。细胞衰老是生命的基本现象，是机体对肿瘤发展的一种防御机制。诱导肿瘤细胞衰老成为防治肿瘤的新思路。研究表明类胰岛素生长因子-1（IGF-1）在肿瘤发生发展起重要促进作用。但阻断或削弱IGF-1信号通路则导致模式生物个体延缓衰老。目前尚无清楚的分子机理来诠释IGF-1的双重功能。我们的前期研究发现IGF-1促进细胞增殖与存活；而长期的强IGF-1信号则诱导依赖于SIRT1和p53的细胞早衰。进一步研究发现 IGF-1抑制SIRT1，导致p53 乙酰化和转录活性增加。我们的假说是：IGF-1诱导的细胞衰老是肿瘤发生发展中的重要的负调控机制，p53是监控IGF-1双功能的分子开关。本项目将阐明IGF-1抑制SIRT1的分子机制；研究IGF-1-SIRT1-p53通路在体内对肿瘤发生发展的影响；以及其与人肿瘤发生发展的相关性，为癌症检测与治疗提供新思路和方法。

胰岛素样生长因-1 （IGF-1) 具有刺激生长和促进衰老的双重生理功能，而去乙酰化蛋白SIRT1及其下游调控靶点抗肿瘤蛋白p53 是调控生长和衰老的关键蛋白。本项目拟深入研究IGF-1-SIRT1-p53信号通路在细胞/器官/个体衰老过程中的关键作用和分子机制。主要研究内容包括（1）阐明IGF-1 调控SIRT1 酶活的分子机理及在细胞早衰过程中的关键作用；（2）建立IGF-1 在细胞早衰及肿瘤形成过程中的动物模型，并研究IGF-1-SIRT1-p53 信号通路在动物衰老和肿瘤发生发展中的作用；（3）研究与人类长寿相关的IGF-1R 突变对细胞早衰和肿瘤形成的影响。本研究原创性的发现（1）IGF-1持续激活诱导依赖于SIRT1的细胞衰老，进而导致器官衰老和个体衰老;（2）IGF-1 特异诱导SIRT1-T177磷酸化，阻断SIRT1入核，从而导致p53乙酰化增加并激活p53转录活性，促进细胞早衰;(3)IGF-1通过促进RhoA 激酶的蛋白表达，激活下游ROCK1 蛋白激酶活性，导致SIRT1-T177 磷酸化；(4) IGF-1 转基因小鼠呈现器官(skin)早衰及个体行为和认知能力的早衰，(5)激活SIRT1以及热量限制可以有效干预 IGF-1 介导的细胞/器官/个体的早衰。这一研究为开发器官衰老标志物和筛选新的抗衰老药物提供了理论基础和新的靶点，并为延缓增龄相关的健康减损提供了新的动物模型，和新的干预/预防策略。