Oncogenic role of the ICK-GSK3beta signaling pathway

ICK-GSK3beta 信号通路的致癌作用

基本信息

批准号：
9206147
负责人：
Zheng Fu
金额：
$ 17.18万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-14 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9206147
关键词：
Address Adenomatous Polyps Attenuated Biological Assay CCI-779 Cell Cycle Cell Proliferation Cells Colon Carcinoma Colonic Neoplasms Colorectal Cancer Complex Data Development Diagnosis Disease Drug resistance FRAP1 gene Feedback Genetic Transcription Goals Grant Growth Growth Factor Human Impairment In Vitro Intervention Intestinal Neoplasms Intestines Knowledge Laboratories Malignant - descriptor Malignant Neoplasms Mediating Molecular Mucous Membrane Mus Neoplastic Cell Transformation Nuclear Oncogenic Outcome Outcome Study Pathway interactions Pharmacology Phosphorylation Phosphorylation Site Phosphotransferases Play Publishing Regulation Relapse Resistance Role Signal Pathway Signal Transduction Sirolimus Site Source Specimen TSC1/2 gene Testing Transcriptional Activation Translations Up-Regulation WNT Signaling Pathway Work Xenograft Model Xenograft procedure adenoma base beta catenin cancer cell cancer therapy carcinogenesis cell growth design driving force gain of function improved improved outcome in vivo in vivo Model innovation intestinal crypt intestinal epithelium knock-down loss of function mTOR Inhibitor mTOR inhibition mimetics mortality mouse model mutant neoplastic cell new therapeutic target novel novel therapeutic intervention overexpression prevent public health relevance subcutaneous tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the third most common malignancy and fourth most common cause of mortality worldwide, and there is an urgent need of new therapeutic approaches for this devastating disease. Although many signaling pathways with important roles in CRC have been identified, there are still major gaps in our understanding about how these pathways functionally network and interplay during malignant transformation of the intestinal epithelium. Our long-term goal is to identify key missing components in this complex signaling puzzle to advance our understanding of the molecular mechanism underlying colon cancer. The objective of this proposal is to explore the role of a novel signaling pathway ICK-GSK3β in the development of colon cancer and tumor resistance to rapalogs. Our central hypothesis is that deregulated ICK-GSK3β signaling axis plays a pivotal role in intestinal neoplasia by transducing aberrant Wnt signals to mTOR hyper-activation through inhibitory phosphorylation of GSK3β-T7 and by mediating a novel feedback mechanism underlying rapamycin resistance in colon cancer therapy. This hypothesis was formulated on the basis of our recent published and preliminary data: 1) ICK, a Wnt transcriptional target, is highly over-expressed in human colon cancer specimens and mouse intestinal adenomas; 2) Knockdown of ICK expression in human colon cancer cells effectively attenuated malignant proliferation in vitro and subcutaneous tumor growth in vivo; 3) Disrupting ICK signaling in colon cancer cells impaired mTOR and Wnt activation; 4) GSK3β, a key component of both Wnt and mTOR pathways, is a novel substrate for ICK; 5) Elevated phosphorylation of GSK3β-T7 by ICK was observed in human CRC specimens as compared with adjacent normal mucosa and in human colon cancer cells after rapamycin treatment. To test this hypothesis, we propose the following two specific aims: Aim-1 will determine whether ICK is able to activate mTOR signaling in colon cancer cells through targeting a novel inhibitory phosphorylation site on GSK3β; Aim-2 will determine whether the ICK-GSK3β signaling axis is important for aberrant Wnt signal-induced intestinal malignancy and rapamycin resistance. Our proposed work is significant because our aims will address major knowledge gaps in our understanding of the mechanisms underlying Wnt activation of mTOR, inhibitory phosphorylation and regulation of GSK3β, and rapamycin resistance. Our proposed work is innovative because our aims may identify inhibitory phosphorylation of Thr-7 as a novel regulatory mechanism for GSK3β, and rapamycin-induced feedback up-regulation of GSK3β-T7 phosphorylation as an innovative mechanism underlying rapamycin resistance. Anticipated outcomes may exert significant impacts on the understanding of the signaling mechanisms underlying the onset and development of colon cancer as well as the design for more effective combination molecular therapy to overcome drug resistance and prevent tumor relapse.

描述（由适用提供）：结直肠癌（CRC）是全球第三大最常见的恶性肿瘤，也是第四大死亡原因，并且迫切需要采用这种毁灭性疾病的新治疗方法。尽管已经确定了许多在CRC中具有重要作用的信号通路，但我们对这些途径在肠上皮的恶性转化过程中如何在功能上网络和相互作用如何在肠上皮细胞的情况下仍存在重大差距。我们的长期目标是在这个复杂的信号拼图中确定关键的缺失成分，以促进我们对结肠癌基础机制的理解。该提案的目的是探索新型信号通路ICK-GSK3β在结肠癌发展和抗乳腺癌肿瘤耐药性中的作用。 Our central hypothesis is that deregulated ICK-GSK3β signaling axis plays a pivotal role in intestinal neoplasia by Transducing aberrant Wnt signals to mTOR hyper-activation through inhibitory phosphorylation of GSK3β-T7 and by mediating a novel feedback mechanism underlying rapamycin resistance in colon cancer therapy.该假设是基于我们最近发表和初步数据的基础提出的：1）iCk，一个转录靶标，在人类结肠癌标本和小鼠肠道腺瘤中高度表达； 2）在人类结肠癌细胞中敲低ICK表达有效地减弱了体内的恶性增殖和皮下肿瘤的生长； 3）破坏结肠癌细胞中的ICK信号传导受损的MTOR和WNT激活； 4）GSK3β是Wnt和MTOR途径的关键组成部分，是ICK的新型底物。 5）与雷帕霉素治疗后相邻的正常粘膜和人类结肠癌细胞相比，在人CRC标本中观察到ICK升高GSK3β-T7的磷酸化。为了检验这一假设，我们提出以下两个具体目的：AIM-1将通过针对GSK3β上的新型抑制性光疗位点来激活结肠癌细胞中的MTOR信号传导； AIM-2将确定ICK-GSK3β信号轴是否对于异常的Wnt信号诱导的肠道恶性肿瘤和雷帕霉素的耐药性很重要。我们提出的工作很重要，因为我们的目标将解决我们对MTOR激活，抑制性磷酸化和GSK3β和雷帕霉素耐药性的WNT激活机制的主要知识差距。我们提出的工作具有创新性，因为我们的目的可以将THR-7的抑制作用磷酸化为GSK3β的新型调节机制，而雷帕霉素诱导的GSK3β-T7磷酸化的反馈上调是一种创新的雷帕霉素抗性的创新机制。预期的结果可能对结肠癌发作和发展的信号传导机制以及更有效的组合分子疗法的设计产生重大影响，以克服耐药性并预防肿瘤释放。