aPKC function in Hedgehog signaling and basal cell carcinoma

aPKC 在 Hedgehog 信号传导和基底细胞癌中的功能

• 批准号: 9034140
• 负责人: Scott Atwood
• 金额: $ 23.54万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-11 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9034140
• 关键词: Allografting; Basal cell carcinoma; Binding Sites; Biochemistry; Biological Models; Cell Line; Cell Polarity; Cessation of life; DNA Binding; Data; Defect; Development; Drug resistance; Environment; Epithelial; Erinaceidae; Exhibits; Gene Targeting; Genes; Genetic; Goals; Growth; Hair follicle structure; Human; Laboratories; Length; Ligand Binding; Link; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Molecular Biology; Mus; Mutation; Nature; Neoplasm Metastasis; Nuclear; Oncogenes; Organ; Organism; Pathway interactions; Pattern; Peptides; Phase; Phosphorylation; Post-Translational Protein Processing; Process; Proteins; Proteomics; Reagent; Research; Resistance; Retirement; Scaffolding Protein; Signal Pathway; Signal Transduction; Skin Cancer; Specificity; Stem cells; Testing; Therapeutic; Transcription Coactivator; Transducers; Tumor Cell Invasion; Vertebrates; Work; Zinc Fingers; abstracting; atypical protein kinase C; drug discovery; human SMO protein; inhibitor/antagonist; migration; new therapeutic target; next generation sequencing; novel; novel therapeutics; overexpression; protein kinase C iota; receptor; smoothened signaling pathway; stem cell fate; therapeutic target; transcription factor; tumor; tumor growth

Project Summary/Abstract: Basal cell carcinoma (BCC) is the most prevalent cancer in the world and nearly half of US citizens are likely to develop this cancer before retirement. BCCs are invasive epithelial tumors that originate from activating mutations in the Hedgehog (Hh) pathway, an essential developmental pathway that has been implicated in approximately 25% of all human cancer deaths. Despite the critical nature of Hh signaling, how Hh mediates the impressive proliferative defects in cancers remain poorly understood. Hh pathway activation begins when Hh ligand binds and inhibits transmembrane receptor Patched1, allowing signal transducer Smoothened (Smo) to activate Gli transcription factors and amplify expression of Hh target genes. Smo inhibitors have recently gained approval for treatment of late advanced or metastatic BCC and exhibit potent tumor regression. While these inhibitors are effective in naïve tumors, aggressive tumors tend to develop early resistance to the drug, illustrating the need for new therapeutic targets. I have recently discovered that a critically important oncogene, atypical Protein Kinase C iota/lambda (aPKC-ι/λ), involved in stem cell fate choice during development of nearly all multicellular organisms is essential for high, sustained Hh pathway activation in BCCs. I have also shown pharmacological inhibition of aPKC suppresses murine BCC tumor growth and the growth of naïve and Smo-resistant BCC cells. The goal of my research is to determine the mechanisms that allow the polarity protein aPKC-ι/λ to promote Hh pathway activation and naïve and Smo-resistant BCC growth. During the K99 phase, I will determine how phosphorylation of Gli by aPKC-ι/λ alters target gene specificity to promote tumor growth, how BCC's regulate aPKC-ι/λ activity, and test the therapeutic potential of additional novel aPKC-ι/λ inhibitors for the treatment of naïve and resistant BCC. During the R00 phase, I will determine how aPKC-ι/λ -dependent Gli1 responsive genes regulate tumor invasion and analyze aPKC-ι/λ function in Smo-resistant BCCs. The results of this study will reveal conserved mechanisms that govern cell polarity and Hh signaling during BCC that will prove invaluable in generating novel therapeutics for the treatment of Hh-dependent cancers.

基底细胞癌（BCC）是世界上最常见的癌症， 一半的美国人可能在退休前患上这种癌症。基底细胞癌是侵袭性上皮肿瘤， Hedgehog（Hh）途径中的激活突变，这是一种重要的发育途径， 与大约25%的人类癌症死亡有关。尽管Hh具有批判性 然而，Hh如何介导癌症中令人印象深刻的增殖缺陷仍然知之甚少。Hh 当Hh配体结合并抑制跨膜受体Patched 1时，通路激活开始， Smo信号转导子激活Gli转录因子并扩增Hh靶表达 基因. Smo抑制剂最近已被批准用于治疗晚期或转移性BCC， 显示出有效的肿瘤消退。虽然这些抑制剂对初治肿瘤有效，但侵袭性肿瘤往往 对药物产生早期耐药性，说明需要新的治疗靶点。我最近 发现了一个非常重要的致癌基因，非典型蛋白激酶C i ota/λ（aPKC-1/λ），参与了 在几乎所有多细胞生物体发育过程中，干细胞命运选择对于高、持续的 BCC中的Hh通路活化。我还发现药理学抑制aPKC抑制小鼠 BCC肿瘤生长以及幼稚和Smo耐药BCC细胞的生长。我研究的目的是 确定允许极性蛋白aPKC-1/λ促进Hh通路活化的机制， 原始和抗Smo BCC生长。在K99阶段，我将确定Gli的磷酸化是如何通过 aPKC-1/λ改变靶基因特异性以促进肿瘤生长，BCC如何调节aPKC-1/λ活性，以及 测试其他新型aPKC-1/λ抑制剂用于治疗初治和耐药的 BCC。在R 00阶段，我将确定aPKC-1/λ依赖的Gli 1应答基因如何调节肿瘤细胞， 并分析Smo耐药BCC中aPKC-1/λ功能。这项研究的结果将揭示保守的 在BCC过程中控制细胞极性和Hh信号传导的机制，将证明在产生 用于治疗Hh依赖性癌症的新疗法。