Novel Mechanisms of Nuclear Phosphoinositide Signaling in the Regulation of the YAP/TAZ Pathway in Triple-Negative Breast Cancer

核磷酸肌醇信号传导调节三阴性乳腺癌 YAP/TAZ 通路的新机制

基本信息

批准号：
10714241
负责人：
Suyong Choi
金额：
$ 28.09万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-16 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714241
关键词：
1-Phosphatidylinositol 4-Kinase Affect Amino Acids Apoptosis Binding Biochemical Biological Biological Assay Biological Process Breast Cancer Cell CRISPR/Cas technology Cell Death Cell Nucleus Cell Proliferation Cell Survival Cell model Cells Coupled Development Drug Targeting Enzymes Family G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Genes Genetic Transcription Goals Growth Homologous Gene Human Inositol Phosphates Integrins Investigation Investments Isomerism Knock-out Knowledge Lead Lipids Malignant Neoplasms Measures Mediating Methods Modeling Molecular Molecular Target Mus Mutagenesis Nature Nebraska Normal Cell Nuclear Oncogenic PI3 gene PIK3CG gene Pathogenesis Pathology Pathway interactions Patients Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphoinositide Pathway Phosphorylation Phosphotransferases Physiology Proteins Regulation Research Role Route Signal Transduction Site Testing Therapeutic Transcription Coactivator Transcriptional Coactivator with PDZ-Binding Motif Xenograft procedure cancer cell cancer therapy cancer type cell motility chemotherapy cofactor functional outcomes genetic signature malignant breast neoplasm migration mouse model mutant new therapeutic target novel novel therapeutic intervention pharmacologic phosphatidylinositol 4-phosphate phosphatidylinositol phosphate 4-kinase programs receptor targeted cancer therapy targeted treatment transcription factor transcriptome sequencing triple-negative invasive breast carcinoma tumor progression tumorigenesis understudied cancer

项目摘要

Project Summary: “Novel Mechanisms of Nuclear Phosphoinositide Signaling in the Regulation of the YAP/TAZ Pathway in Triple-Negative Breast Cancer” Phosphoinositides (PIs) are lipid messengers that control many aspects of human physiology. A significant fraction of PIs (>40% of total PIs) is found in the nucleus, however the nature and functions of the nuclear PIs are largely unknown. We discovered that phosphatidylinositol 4,5-bisphosphate (PI4,5P2) is an abundant PI species in the nucleus and the PI4,5P2-generating kinase phosphatidylinositol-4-phosphate-5-kinase type 1 alpha (PIPKI) is a major enzyme modulating nuclear PI4,5P2 signaling. Nuclear PI4,5P2 can be further phosphorylated by a nuclear-localizing PI3-kinase (PI3K) inositol phosphate multikinase (IPMK) to produce a PI species, PI3,4,5P3, that has been implicated in oncogenesis. This suggests that PIPKI and IPMK are potential targets for cancer therapy. Consistently, we showed that depletion or pharmacological inhibition of PIPKI and IPMK leads to cancer cell death by apoptosis in triple negative breast cancer (TNBC) cells. Moreover, in TNBC cells, we discovered that depletion of PIPKI and IPMK significantly reduces the expression of YAP/TAZ target genes that have established contributions to oncogenesis. TNBC is the most aggressive subtype of breast cancer and associated with poor patient survival due to lack of alternatives to current chemotherapies. As a result, there is an urgent need for discovering novel targeted therapeutics in TNBC. The YAP/TAZ-PI kinases (PIPKI and IPMK) pathways are attractive drug targets because 1) aberrant activation of YAP/TAZ is frequently found in breast cancer particularly in TNBC, PIPKI gene is commonly amplified in TNBC, and 2) the nuclear PI3,4,5P3 pathway is frequently dysregulated in TNBC. Precise understanding of nuclear PIs-mediated YAP/TAZ pathway will provide knowledge which can be utilized for developing targeted therapeutics against TNBC. In this proposal, we will 1) elucidate molecular mechanisms by which the YAP/TAZ pathway is controlled by PIPIK and IPMK via extensive biochemical and cell biological approaches and 2) investigate contributions of PIPIK and IPMK in TNBC pathogenesis in cultured TNBC cells and mouse models. This project will provide pivotal information how the YAP/TAZ pathway is regulated by the PI signaling and illuminate new routes to target the YAP/TAZ pathway in cancer by the understudied kinases of PIPIK and IPMK.

项目摘要：“核磷酸肌醇信号调节的新机制” 三阴性乳腺癌中的 YAP/TAZ 通路” 磷酸肌醇 (PI) 是控制人体生理机能许多方面的脂质信使。部分 PI（> 总 PI 的 40%）存在于细胞核中，但是核 PI 的性质和功能我们发现磷脂酰肌醇 4,5-二磷酸 (PI4,5P2) 是一种丰富的 PI。细胞核中的物种和 PI4,5P2 生成激酶 1 型磷脂酰肌醇-4-磷酸-5-激酶 α (PIPKIα) 是调节核 PI4,5P2 信号传导的主要酶。核 PI4,5P2 可以进一步调节。被核定位 PI3 激酶 (PI3K) 磷酸肌醇多激酶 (IPMK) 磷酸化，产生 PI PI3,4,5P3 与肿瘤发生有关，这表明 PIPKI 和 IPMK 具有潜在的潜力。一致地，我们表明 PIPKIα 的消耗或药物抑制。 IPMK 通过三阴性乳腺癌 (TNBC) 细胞凋亡导致癌细胞死亡。细胞中，我们发现 PIPKI 和 IPMK 的耗竭显着降低了 YAP/TAZ 靶标的表达已确定对肿瘤发生有贡献的基因 TNBC 是最具侵袭性的乳腺亚型。癌症并与由于缺乏当前化疗的替代方案而导致的患者生存率较差有关。因此，迫切需要发现 TNBC 的新型靶向疗法 YAP/TAZ-PI 激酶。（PIPKI 和 IPMK）途径是有吸引力的药物靶点，因为 1) YAP/TAZ 的异常激活经常发生在乳腺癌中尤其是在 TNBC 中发现，PIPKI 基因通常在 TNBC 中扩增，并且 2) 核 TNBC 中 PI3,4,5P3 通路经常失调准确理解核 PI 介导的 YAP/TAZ。途径将提供可用于开发针对 TNBC 的靶向疗法的知识。提案中，我们将 1) 阐明 PIPIK 控制 YAP/TAZ 通路的分子机制和 IPMK 通过广泛的生化和细胞生物学方法，2) 研究 PIPIK 的贡献和 IPMK 在培养 TNBC 细胞和小鼠模型中的 TNBC 发病机制。了解 YAP/TAZ 通路如何受 PI 信号传导调节，并阐明靶向该通路的新途径通过正在研究的 PIPIKα 和 IPMK 激酶在癌症中的 YAP/TAZ 通路。