Novel Mechanisms of Nuclear Phosphoinositide Signaling in 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

• 批准号: 10579376
• 负责人: Suyong Choi
• 金额: $ 36.88万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2023-07-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10579376
• 关键词: 1-Phosphatidylinositol 3-Kinase; 1-Phosphatidylinositol 4-Kinase; Amino Acids; Apoptosis; Binding; Biochemical; Biological; Biological Assay; Biological Process; Breast Cancer Cell; Breast Cancer Treatment; CRISPR/Cas technology; Cell Death; Cell Nucleus; Cell Proliferation; Cell model; Cells; Development; Drug Targeting; Enzymes; Gene Expression; Genes; Human; Inositol Phosphates; Investigation; Knock-out; Knowledge; Lipids; Mediating; Molecular; Molecular Target; Mus; Mutagenesis; Nature; Nebraska; Nuclear; PI3 gene; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phosphatidylinositols; Phosphoinositide Pathway; Phosphotransferases; Physiology; Proteins; Regulation; Signal Transduction; Site; Therapeutic; Xenograft procedure; base; breast cancer progression; cancer cell; cell motility; chemotherapy; druggable target; functional outcomes; malignant breast neoplasm; method development; mouse model; mutant; new therapeutic target; novel; phosphatidylinositol phosphate 4-kinase; targeted cancer therapy; targeted treatment; therapeutic development; transcriptome sequencing; triple-negative invasive breast carcinoma; tumorigenesis

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 aberrant activation of YAP/TAZ is frequently found in breast cancer particularly in TNBC, PIPKI􀁄 gene is commonly amplified in TNBC, and the nuclear PI3,4,5P3 pathway is frequently deregulated 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.

磷酸肌醇（PIS）是控制人类生理许多方面的脂质信使。重要的 在核中发现了PI的比例（> 40％的PI），但是核的性质和功能 PI在很大程度上未知。我们发现磷脂酰肌醇4,5-双磷酸（PI4,5P2）是 核中最丰富的Pi物种和PI4,5P2生成激酶磷脂酰肌醇-4-磷酸-5-- 激酶1型α（PIPKI◎）是调节核PI4,5P2信号传导的主要酶。核Pi4,5p2可以 通过核位置PI3-激酶（PI3K）肌醇磷酸多激酶（IPMK）进一步磷酸化 为了产生PI物种，PI3,4,5p3在肿瘤发生中已暗示。这表明Pipki◎。 IPMK是癌症治疗的潜在靶标。一贯，我们表明耗尽或 PIPKI◎◎和IPMK的药理抑制作用导致三重阴性的细胞凋亡导致癌细胞死亡 乳腺癌（TNBC）细胞。此外，在TNBC细胞中，我们发现PIPKI和IPMK的耗竭 显着降低了已确立贡献的YAP/TAZ靶基因的表达 肿瘤发生。 TNBC是乳腺癌最具侵略性的亚型，并且患者不良 由于缺乏当前化学疗法的替代方法而导致的生存。结果，迫切需要 在TNBC中发现了新的靶向疗法。 YAP/TAZ-PI激酶（PIPKI和IPMK）途径 是有吸引力的药物目标，因为在乳腺癌中经常发现YAP/TAZ的异常激活 特别是在TNBC中，pipki◎Gen通常在TNBC中扩增，并且核PI3,4,53途径为 在TNBC中经常放松管制。对核PI介导的YAP/TAZ途径的精确理解将 提供可用于开发针对TNBC的靶向疗法的知识。在这个 提案，我们将1）阐明由YAP/TAZ途径控制的分子机制 Pipik◎和IPMK通过广泛的生化和细胞生物学方法以及2）研究贡献 培养的TNBC细胞和小鼠模型中TNBC发病机理中的Pipik◎和IPMK的of。