Regulation of breast cancer cell metabolism by an alternate cap-dependent mechanism of translation initiation.

项目摘要/摘要 翻译控制和代谢重编程是晚期癌症的特征。许多重要的基因 参与癌症发展和进展的方方面面表达选择性翻译的mRNAs 调节，包括癌细胞新陈代谢的调节。癌细胞获得了一种改变的新陈代谢， 从氧化磷酸化(OXPHOS)到糖酵解表型(Warburg效应)，以增加对 生产氨基酸、脂质、核酸和能量的替代代谢途径，以支持 生长、增殖和转移。三阴性乳腺癌(TNBC)，最具侵袭性和高度 转移性BC亚型预后最差，以糖酵解升高和低OXPHOS为特征。 TNBC模型和患者样本的特征是糖酵解异常 它链接到 化疗耐药。尽管如此，这种代谢变化发生的确切机制在很大程度上尚不清楚。 使用TNBC细胞模型表明，帽依赖但mTORC1/eIF4E-的另一种机制- 通过DAP5-eIF3d复合体独立的mRNA翻译调节几个mRNAs，包括那些参与 葡萄糖代谢。这项应用提出了研究乳房翻译调节的重要作用 癌细胞通过DAP5/eIF3d复合体的代谢。中心假说是DAP5/eIF3d在 调节从氧化磷酸化到有氧糖酵解的转换，这是代谢途径中必不可少的 转移，乳腺癌和所有类型癌症的主要死亡原因。在这份SC2提案中，PI提议 了解DAP5-eIF3d复合体在翻译调节涉及的关键mRNAs中的重要作用 TNBC模型癌细胞代谢的实验研究。核心假设将通过追求三个具体目标来检验：(1) 确定DAP5/eIF3d在机体从氧化磷酸化到有氧糖酵解的代谢转换中的作用 (2)鉴定DAP5/eIF3d调控细胞周期的分子机制。 与癌细胞代谢相关的mRNAs的翻译以及(3)利用人类原发肿瘤活检组织 转移的TNBCs验证DAP5/eIF3d靶点并与代谢分子生物标记物相关。这个 本申请中提出的研究具有创新性，因为它侧重于理解一种新的帽子形成机制。 转移性癌细胞代谢调控中的依赖信使核糖核酸翻译这是非常重要的 因为选择性翻译启动在癌症代谢中的作用几乎完全没有被研究过。最终， 这样的知识有可能识别一种新的机制，通过这种机制选择性地调节翻译启动 推动TNBC转移，并最终将提供新的发展机会，创新的治疗方法 以代谢失调为特征的晚期乳腺癌。

Project Summary/Abstract Translational control and metabolic reprogramming are hallmarks of advanced cancers. Many important genes involved in all aspects of cancer development and progression express mRNAs that are selectively translationally regulated, including regulators of cancer cell metabolism. Cancer cells acquire an altered metabolism, switching from oxidative phosphorylation (OXPHOS) to glycolytic phenotype (Warburg effect), to increase reliance on alternate metabolic pathways for production of amino acids, lipids, nucleic acids and energy in order to support growth, proliferation and metastasis. Triple-negative breast cancer (TNBC), one the most aggressive and highly metastatic subtypes of BC with the poorest outcome, is characterized by elevated glycolysis and low OXPHOS. TNBC models and patient samples are characterized by dysregulated glycolysis which is linked to chemotherapeutic resistance. Still, the exact mechanism by which this metabolic switch occurs is largely unknown. Using a TNBC cell model, it has been shown that an alternate mechanism of cap-dependent but mTORC1/eIF4E- independent mRNA translation via DAP5-eIF3d complexes modulates several mRNAs including those involved in glucose metabolism. This application proposes to study the important role of translational regulation of breast cancer cell metabolism by the DAP5/eIF3d complex. The central hypothesis is that DAP5/eIF3d is critical in regulating the switch from Ox-Phosphorylation to aerobic glycolysis, which are metabolic pathways essential for metastasis, the principal cause of death in breast and all types of cancer. In this SC2 proposal, the PI proposes to understand the important role of the DAP5-eIF3d complex in the translational regulation of key mRNAs involved in cancer cell metabolism of TNBC models. The central hypothesis will be tested by pursuing three specific aims: (1) Determine the role of DAP5/eIF3d in the metabolic switch from oxidative phosphorylation to aerobic glycolysis in well characterized TNBC cell lines; (2) Identify the molecular mechanism by which DAP5/eIF3d modulates the translation of mRNAs associated with cancer cell metabolism and (3) Utilize human primary tumor biopsies of metastasized TNBCs to validate DAP5/eIF3d targets and correlated with metabolic molecular biomarkers. The research proposed in this application is innovative, because it focuses on understanding a new mechanism of cap- dependent mRNA translation in the regulation of metastatic cancer cell metabolism. This is highly significant because the role of selective translation initiation in cancer metabolism is almost completely unexplored. Ultimately, such knowledge has the potential of identify a novel mechanism by which selective regulation of translation initiation drives TNBC metastasis and eventually will offer new opportunities for development innovative therapies to treat advanced breast cancer characterized by dysregulated metabolism.