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（由申请人提供）：大肠癌（CRC）是第三个Mosth恶性肿瘤，第四个最常见的原因在全球范围内，迫切需要对CRC的新治疗方法。途径在肠上皮的马利尼亚人的形成期间，我们对分子机械结肠癌的长期。我们的中心假设是，通过将异常的Wnt信号转换为MTOR激活的硫代硫代磷酸化，通过介导NoeDback机制，将ICK-GSK3β信号轴发挥着关键作用。转录靶标在人类结肠癌的规格和小鼠肠道腺瘤中高度表达；与邻近的正常粘膜相比，在人类CRC标本中观察到ICK的Wnt激活升高； ICK是通过针对GSK3β的新型抑制性磷酸化位点来激活结肠癌细胞中的MTOR信号。，雷帕霉素的耐药性。克服耐药性并防止肿瘤复发。