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

摘要 众所周知，癌症的代谢是高度动态的，并且依赖于上下文和癌基因。然而， 癌基因依赖性代谢中的潜在机制，特别是细胞器间通讯的机制 重新编程，在很大程度上是未知的。我们的初步研究证实致癌的MYC调节 内质网定位的跨膜传感器IRE1α及其底物XBP1通过多个 机械装置。重要的是，我们的初步研究表明，myc过度表达三重基因的易感性增加。 阴性乳腺癌对IRE1α/XBP1的抑制，可能是通过细胞器改变介导的 与脂肪酸氧化的沟通和代谢重新编程(粮农组织)。这些发现提供了一个 寻求对内质网、线粒体和线粒体之间这种改变的通信的生物学洞察的框架 在MYC过表达的TNBC细胞中的核，并进一步探讨药物抑制作用。 IRE1α作为一种通过干扰细胞器间通讯来对抗MYC驱动的TNBC的肿瘤方法。我们 假设致癌MYC劫持内质网应激传感器IRE1α及其底物XBP1，以促进 线粒体粮农组织和维持TNBC肿瘤发生和对化疗的耐药性。这项提议将 阐明内质网在MYC驱动的致癌应激和线粒体中的作用及机制 TNBC中的代谢重编程。在目标1中，我们将研究IRE1α/XBP1的生物学意义 MYC驱动的TNBC中介导的内质网-核通讯。目标2将确定线粒体粮农组织的作用 在MYC驱动的肿瘤细胞中IRE1α/XBP1通路的激活。最后，Aim 3将研究体内疗效 IRE1、α抑制剂和多西紫杉醇联合治疗恶性黑色素瘤的作用机制。这个 这项提议产生的数据将是重要的，因为它们将促进新的、机制的发展-- 以此为基础的治疗方法来扰乱这些改变的代谢途径，并改善MYC的治疗- 推动了TNBC。

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.