MNSOD ACETYLATION PROMOTES CANCER STEM CELL PHENOTYPES IN BREAST CANCER

MNSOD 乙酰化促进乳腺癌干细胞表型

• 批准号: 10193167
• 负责人: Marcelo G Bonini
• 金额: $ 35.23万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-14 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10193167
• 关键词: Abbreviations; Acetylation; Advisory Committees; Aging; Antioxidants; Behavior; Biochemical; Biochemical Process; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Patient; Cancer Patient; Cells; Characteristics; Chemicals; Chicago; Clinical; Collection; Development; Diffuse; Disease; Doxorubicin; Drug resistance; Enzymes; Estrogen Receptors; Exhibits; Genetic; Hand; Hydrogen Peroxide; Hypoxia; Laboratories; Lead; Link; Lysine; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metabolic; Metabolic stress; Metastatic breast cancer; Mitochondria; Molecular; Molecular Profiling; Molecular Target; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Normal tissue morphology; Oncoproteins; Oxidative Stress; Paclitaxel; Patients; Peroxidases; Pharmacotherapy; Phenotype; Post-Translational Protein Processing; Primary Neoplasm; Production; Reactive Oxygen Species; Records; Recurrence; Reporting; Research; Resistance; Resistance development; Risk; Role; SOD2 gene; Sampling; Signal Transduction; Structure; Testing; Transgenes; Translating; Treatment Failure; Tumor Suppressor Proteins; Urban Hospitals; Woman; base; cancer stem cell; cancer subtypes; catalase; cohort; conventional therapy; epidemiology study; ethnic diversity; follow-up; gain of function; malignant breast neoplasm; malignant phenotype; mitochondrial metabolism; monomer; mouse model; mutant; neoplastic cell; new therapeutic target; novel; prevent; response; restoration; standard of care; stem; stem cells; stem-like cell; stemness; therapeutic target; tumor; tumor initiation; tumor progression

PROJECT SUMMARY / ABSTRACT: Cancer stem cells are a rare and yet critically important subpopulation of cells in tumors associated with treatment failure and metastatic recurrence. Though it is becoming increasingly clear that targeting this subpopulation could lead to therapies with better odds of a cure it is still unknown how these cells originate and what are the biochemical processes that promote “stemness” in cancer. Our laboratory found that alterations in the metabolism of mitochondrial reactive oxygen species (ROS) promote aberrant activation of hypoxia-induced factor 2α (HIF2α). The activation of HIF2α is a well-established mechanism of stemness that has also been implicated in metastatic recurrence as well as treatment failure in women with breast cancer. We found that a posttranslational modification (i.e. acetylation) of a primary enzyme involved in the metabolism of mitochondrial ROS, manganese superoxide dismutase (MnSOD) breaks the tetrameric structure that has antioxidant function turning the enzyme into a monomer that promotes ROS formation and activates HIF2α. We also found that MnSOD-K68Ac accumulates prominently in breast cancers expressing low estrogen receptor levels. Hence, it is proposed that MnSOD has a dichotomous behavior functioning as a suppressor of tumor initiation (antioxidant function) and yet promotes cancer stem cell reprogramming later on in established tumors. This proposition is supported by the finding of strong associations between a MnSOD/HIF2α signature present in metastatic lesions compared to primary tumor samples from the same breast cancer patients. Hence, this application aims at determining: (1) if MnSOD-Ac reprograms tumor cells to stem-like phenotypes associated with chemoresistance. (2) if the biochemical and/or genetic targeting of MnSOD-Ac or HIF2α in established tumors of mice with the MnSODhigh/HIF2α signature (MMTV.PyVT) suppresses chemoresistance and/or metastasis. (3) if there is an association between subsets of women with breast cancer that exhibit a MnSODhigh or MnSOD-Ac, or MnSOD-ROS-HIF2α molecular axis signature and develop chemoresistance or have increased risk of metastatic recurrence.

项目摘要/摘要： 癌症干细胞是肿瘤中罕见但极其重要的细胞亚群 与治疗失败和转移复发有关。尽管它变得越来越 显然，针对这一亚群可能会导致治愈率更高的疗法，但目前仍然如此 未知这些细胞是如何起源的以及促进的生化过程是什么 癌症中的“干性”。我们的实验室发现线粒体代谢的改变 活性氧 (ROS) 促进缺氧诱导因子 2α 的异常激活 （HIF2α）。 HIF2α 的激活是一种成熟的干性机制，也已被证实 与乳腺癌女性的转移复发和治疗失败有关 癌症。我们发现初级酶的翻译后修饰（即乙酰化） 参与线粒体ROS、锰超氧化物歧化酶（MnSOD）的代谢 破坏具有抗氧化功能的四聚体结构，将酶转化为单体 促进 ROS 形成并激活 HIF2α。我们还发现 MnSOD-K68Ac 在表达低雌激素受体水平的乳腺癌中显着积累。因此，它是 提出 MnSOD 具有作为肿瘤抑制因子的二分行为 启动（抗氧化功能），但随后促进癌症干细胞重编程 已形成的肿瘤。这一命题得到了以下发现的强烈关联的支持： 与原发肿瘤样本相比，转移性病变中存在 MnSOD/HIF2α 特征 来自同一个乳腺癌患者。因此，本申请旨在确定： (1) 如果 MnSOD-Ac 将肿瘤细胞重新编程为与化疗耐药相关的干细胞样表型。 (2) 如果 MnSOD-Ac 或 HIF2α 的生化和/或基因靶向已建立的肿瘤 具有 MnSODhigh/HIF2α 特征 (MMTV.PyVT) 的小鼠可抑制化疗耐药性和/或 转移。 (3) 如果患有乳腺癌的女性亚群之间存在关联， 表现出 MnSODhigh 或 MnSOD-Ac 或 MnSOD-ROS-HIF2α 分子轴特征并且 产生化疗耐药性或增加转移复发的风险。