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

项目总结/摘要 翻译控制和代谢重编程是晚期癌症的标志。许多重要基因 参与癌症发展和进展的所有方面的mRNA表达， 调节，包括癌细胞代谢的调节剂。癌细胞获得改变的新陈代谢， 从氧化磷酸化（OXPHOS）到糖酵解表型（瓦尔堡效应），以增加对 用于产生氨基酸、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）是最具侵袭性和高度恶性的乳腺癌之一。 具有最差结果的转移性BC亚型的特征在于糖酵解升高和低OXPHOS。 TNBC模型和患者样品的特征在于糖酵解失调 链接到 化疗耐药性尽管如此，这种代谢转换发生的确切机制在很大程度上是未知的。 使用TNBC细胞模型，已经表明帽依赖性但mTORC 1/eIF 4 E-1的替代机制是一种免疫抑制剂。 通过DAP 5-eIF 3d复合物的独立mRNA翻译调节几种mRNA，包括参与 葡萄糖代谢本申请提出研究乳腺癌的翻译调节的重要作用， 通过DAP 5/eIF 3d复合物的癌细胞代谢。核心假设是DAP 5/eIF 3d在 调节从氧磷酸化到有氧糖酵解的转换，这是代谢途径， 转移是乳腺癌和所有类型癌症死亡的主要原因。在本SC 2建议中，PI建议 了解DAP 5-eIF 3d复合物在参与转录调控的关键mRNA中的重要作用， TNBC模型的癌细胞代谢。中心假设将通过追求三个具体目标来检验：（1） 确定DAP 5/eIF 3d在从氧化磷酸化到有氧糖酵解的代谢转换中的作用， （2）确定DAP 5/eIF 3d调节TNBC细胞系的分子机制; 与癌细胞代谢相关的mRNA的翻译和（3）利用人原发性肿瘤活检组织， 转移的TNBC以验证DAP 5/eIF 3d靶标并与代谢分子生物标志物相关。的 在本申请中提出的研究是创新的，因为它侧重于理解一种新的cap机制， 在转移性癌细胞代谢的调节中依赖于mRNA翻译。这是非常重要的 因为选择性翻译起始在癌症代谢中的作用几乎完全未被探索。最后， 这些知识有可能确定一种新的机制， 推动TNBC转移，最终将为开发创新疗法提供新的机会， 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.