Crosstalk between the ER Stress Response and Mitochondrial Fatty Acid Oxidation in MYC-driven Breast Cancer

MYC 驱动的乳腺癌中 ER 应激反应与线粒体脂肪酸氧化之间的串扰

• 批准号: 10180914
• 负责人: Xi Chen
• 金额: $ 36.26万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-12 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180914
• 关键词: Binding; Biological; Breast Cancer Cell; Breast Cancer Patient; Carnitine; Cell Nucleus; Cell physiology; Cells; Cellular Stress; Combined Modality Therapy; Communication; Consumption; Data; Dependence; Development; Endoplasmic Reticulum; Energy Metabolism; Enhancers; Enzymes; Fatty Acids; Genetic Transcription; Goals; Growth; Impairment; In Vitro; Mediating; Metabolic; Metabolic Pathway; Mitochondria; Modeling; Molecular; Oncogenes; Oncogenic; Organelles; Pathway interactions; Patient-Focused Outcomes; Pharmacology; Pilot Projects; Predisposition; Production; Proteins; Relapse; Research; Resistance; Ribonucleases; Role; Specificity; Stress; Systemic Therapy; Testing; Therapeutic; Toxic effect; Transferase; Treatment Efficacy; XBP1 gene; base; biological adaptation to stress; breast cancer progression; cancer cell; cancer subtypes; cell behavior; chemotherapy; cohort; disorder later incidence prevention; docetaxel; endoplasmic reticulum stress; fatty acid oxidation; improved; in vivo; inhibitor/antagonist; insight; long chain fatty acid; malignant breast neoplasm; novel; novel therapeutic intervention; overexpression; patient derived xenograft model; pre-clinical; promoter; response; sensor; targeted treatment; therapy resistant; triple-negative invasive breast carcinoma; tumor; tumor eradication; tumor growth; tumor metabolism; tumor xenograft; tumorigenesis; uptake

ABSTRACT It is well known that cancer metabolism is highly dynamic and context- and oncogene-dependent. However, the underlying mechanism, particularly that of interorganelle communication in oncogene-dependent metabolic reprogramming, is largely unknown. Our preliminary studies establish that oncogenic MYC regulates Endoplasmic Reticulum (ER)-localized transmembrane sensor IRE1α and its substrate XBP1 via multiple mechanisms. Importantly, our pilot studies suggest the increased susceptibility of MYC-overexpressing triple negative breast cancer (TNBC) to IRE1α/XBP1 inhibition, possibly mediated via altered interorganelle communication and metabolic reprogramming to fatty acid oxidation (FAO). These findings provide a framework to seek biological insight into this altered communication between the ER, mitochondria, and nucleus in MYC-overexpressing TNBC cells, and to further explore the effects of pharmacological inhibition of IRE1α as an anti-tumor approach for MYC-driven TNBC by disrupting the interorganelle communication. We hypothesize that oncogenic MYC hijacks the ER stress sensor IRE1α, and its substrate XBP1, to promote mitochondrial FAO and sustain TNBC tumorigenesis and resistance to chemotherapy. This proposal will elucidate the function and mechanism of the ER in regulating MYC-driven oncogenic stress and mitochondrial metabolic reprogramming in TNBC. In Aim 1, we will investigate the biological significance of IRE1α/XBP1 mediated ER-nucleus communication in MYC-driven TNBC. Aim 2 will determine the role of mitochondrial FAO activation by the IRE1α/XBP1 pathway in MYC-driven TNBC. Lastly, Aim 3 will investigate the in vivo efficacy and mechanisms of combination therapy with IRE1α inhibitor and docetaxel in treating MYC-driven TNBC. The resulting data from this proposal will be significant as they will promote the development of novel, mechanism- based therapeutic approaches to disrupt these altered metabolic pathways and improve the treatment of MYC- driven TNBC.

摘要 众所周知，癌症代谢是高度动态的，并且依赖于背景和癌基因。然而，在这方面， 潜在的机制，特别是癌基因依赖性代谢中细胞器间的通讯机制， 重新编程，在很大程度上是未知的。我们的初步研究表明，致癌MYC调节 内质网（ER）定位的跨膜传感器IRE 1 α及其底物XBP 1通过多个 机制等重要的是，我们的初步研究表明，MYC过表达的三重基因的易感性增加， 阴性乳腺癌（TNBC）对IRE 1 α/XBP 1抑制的影响，可能通过改变的细胞器间 通讯和代谢重编程脂肪酸氧化（粮农组织）。这些发现提供了一个 框架，以寻求对ER，线粒体和线粒体之间这种改变的通信的生物学见解。 细胞核中的MYC-过表达TNBC细胞，并进一步探索药理学抑制MYC的作用。 IRE 1 α通过破坏细胞器间通讯作为MYC驱动的TNBC的抗肿瘤方法。我们 假设致癌MYC劫持ER应激传感器IRE 1 α及其底物XBP 1， 线粒体FAO和维持TNBC肿瘤发生和对化疗的抗性。这项建议会 阐明ER在调节MYC驱动的致癌应激和线粒体中的功能和机制， TNBC中的代谢重编程。目的1：研究IRE 1 α/XBP 1的生物学意义 在MYC驱动的TNBC中介导的ER-核通讯。目标2将确定线粒体粮农组织的作用 在MYC驱动的TNBC中通过IRE 1 α/XBP 1途径激活。最后，目标3将研究体内疗效 IRE 1 α抑制剂联合多西他赛治疗MYC驱动的TNBC的机制。的 从这一建议中得到的数据将是重要的，因为它们将促进新的机制的发展， 基于治疗方法来破坏这些改变的代谢途径，并改善MYC的治疗， 驱动TNBC。