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.

磷脂酰肌醇（PI）是控制人体生理学许多方面的脂质信使。显著 在细胞核中发现了一部分PI（>总PI的40%），然而，细胞核的性质和功能 PI基本上是未知的。我们发现磷脂酰肌醇4，5-二磷酸（PI 4，5 P2）是一种 细胞核中丰富的PI种类和产生PI 4，5 P2的激酶磷脂酰肌醇-4-磷酸-5-磷酸， 1型激酶α（PIPKIα）是调节核PI 4，5 β 2信号传导的主要酶。核PI 4，5 P2可以 被核定位PI 3-激酶（PI 3 K）磷酸肌醇多激酶（IPMK）进一步磷酸化 以产生与肿瘤发生有关的PI物质PI 3，4，5 P3。这表明，PIPKI􀁄 和IPMK是肿瘤治疗的潜在靶点。一致地，我们表明， PIPKIβ和IPMK的药理学抑制导致三阴性细胞中通过凋亡的癌细胞死亡 乳腺癌（TNBC）细胞。此外，在TNBC细胞中，我们发现PIPKIβ和IPMK的消耗 显著降低了雅普/TAZ靶基因的表达，这些靶基因已经确定对 肿瘤发生TNBC是乳腺癌中最具侵袭性的亚型， 由于缺乏目前化疗的替代方案，患者无法存活。因此，迫切需要 在TNBC中发现新的靶向疗法。雅普/TAZ-PI激酶（PIPKI激酶和IPMK）通路 是有吸引力的药物靶点，因为雅普/TAZ的异常激活经常在乳腺癌中发现 特别是在TNBC中，PIPKI基因在TNBC中普遍扩增，并且核PI 3，4，5 P3途径􀁄 在TNBC中经常放松管制。对核PI介导的雅普/TAZ信号通路的准确理解将有助于 提供可用于开发针对TNBC的靶向治疗剂的知识。在这 我们将1）阐明雅普/TAZ通路受以下因素控制的分子机制： 􀁄通过广泛的生物化学和细胞生物学方法研究PIPK和IPMK的作用， 在培养的TNBC细胞和小鼠模型中的TNBC发病机制中的PIPIKβ和IPMK。