Oncogenic role of the ICK-GSK3beta signaling pathway

ICK-GSK3beta 信号通路的致癌作用

• 批准号: 9023974
• 负责人: Zheng Fu
• 金额: $ 20.62万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-14 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9023974
• 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; Goals; Grant; Growth; Human; In Vitro; Intervention; Intestinal Neoplasms; Intestines; Knowledge; Laboratories; Malignant - descriptor; Malignant Neoplasms; Mediating; Mitotic Cell Cycle; Molecular; Mucous Membrane; Mus; Neoplastic Cell Transformation; Nuclear; Oncogenic; Outcome; Outcome Study; Pathway interactions; 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; 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; 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; prevent; public health relevance; subcutaneous; tumor; tumor growth

 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）：结直肠癌（CRC）是全球第三大常见恶性肿瘤和第四大常见死亡原因，迫切需要针对这种毁灭性疾病的新治疗方法。虽然已经确定了许多在CRC中具有重要作用的信号通路，但我们对这些通路在肠上皮恶性转化过程中如何在功能上网络化和相互作用的理解仍然存在重大差距。我们的长期目标是确定这个复杂信号转导难题中的关键缺失成分，以促进我们对结肠癌潜在分子机制的理解。本提案的目的是探索新型信号通路ICK-GSK 3 β在结肠癌发展和肿瘤对雷帕霉素类似物耐药性中的作用。我们的中心假设是，失调的ICK-GSK 3 β信号传导轴通过GSK 3 β-T7的抑制性磷酸化将异常Wnt信号转导至mTOR过度激活，并介导结肠癌治疗中雷帕霉素耐药的新反馈机制，在肠肿瘤中发挥关键作用。这一假设是基于我们最近发表的和初步的数据：1）ICK，一个Wnt转录靶点，在人结肠癌标本和小鼠肠腺瘤中高度过表达; 2）在人结肠癌细胞中敲低ICK表达有效地减弱了体外恶性增殖和体内皮下肿瘤生长; 3）阻断结肠癌细胞中ICK信号通路会损害mTOR和Wnt的激活：4）GSK 3 β是Wnt和mTOR通路的关键组分，是ICK的新底物; 5）与邻近的正常粘膜和雷帕霉素处理后的人结肠癌细胞相比，在人CRC标本中观察到ICK对GSK 3 β-T7的磷酸化升高。为了验证这一假设，我们提出了以下两个具体目标：Aim-1将确定ICK是否能够通过靶向GSK 3 β上新的抑制性磷酸化位点来激活结肠癌细胞中的mTOR信号传导; Aim-2将确定ICK-GSK 3 β信号传导轴是否对异常Wnt信号诱导的肠道恶性肿瘤和雷帕霉素耐药性很重要。我们提出的工作是重要的，因为我们的目标将解决我们理解的mTOR的Wnt激活，抑制性磷酸化和GSK 3 β的调节，以及雷帕霉素抗性的机制的主要知识差距。我们的工作是创新性的，因为我们的目标可能是确定抑制性磷酸化的Thr-7作为一种新的调节机制的GSK 3 β，和雷帕霉素诱导的反馈上调的GSK 3 β-T7磷酸化作为一种创新的机制雷帕霉素耐药。预期的结果可能对理解结肠癌发生和发展的信号机制以及设计更有效的联合分子治疗以克服耐药性和预防肿瘤复发产生重大影响。