Regulation of autophagy in bone metastasis

骨转移中自噬的调控

• 批准号: 10056209
• 负责人: Jitesh Pratap
• 金额: $ 13.4万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056209
• 关键词: Acetylation; Acetylesterase; Address; Affect; Autophagocytosis; Autophagosome; Biochemical Pathway; Bone Diseases; Breast Cancer Cell; Breast cancer metastasis; Cell Survival; Cells; Cessation of life; Data; Deacetylase; Development; Disseminated Malignant Neoplasm; Distant Metastasis; Electrons; Energy-Generating Resources; Fracture; Goals; HDAC6 gene; Histologic; Histone Deacetylase Inhibitor; Impairment; Individual; Lysosomes; Malignant Neoplasms; Mediating; Metabolic; Metastatic Neoplasm to the Bone; Metastatic breast cancer; Microscopic; Microtubule-Associated Proteins; Microtubules; Molecular; Neoplasm Metastasis; Organelles; Outcome; Pathway interactions; Patients; Pharmacology; Property; Regulation; Reporter; Reporting; Site; Starvation; Stress; Testing; Therapeutic; Xenograft procedure; alpha Tubulin; base; bioimaging; bone; bone loss; breast cancer survival; cancer cell; cell motility; confocal imaging; inhibitor/antagonist; malignant breast neoplasm; microCT; mortality; mouse model; mutant; novel; novel strategies; novel therapeutic intervention; overexpression; prevent; programs; trafficking; transcription factor; tumor

Abstract: The specific goal of our proposal is to understand the mechanism of Runt-related factor-2 (Runx2)-mediated autophagy in bone metastasis of breast cancer. Bone is a common target site of distant metastasis of breast cancer. Metastasis to bone results in severe bone loss, fractures, and death of more than 30,000 individuals each year. Recent studies show that metastatic cancer cells induce autophagy to survive stress conditions. Autophagy is a highly regulated mechanism by where cytoplasmic components are degraded by the lysosome for cell survival during starvation. Despite the recent progress, the molecular mechanisms of autophagy during bone metastasis remain poorly understood. Accordingly, our long-term goal is to define the regulation of autophagy and understand how this regulatory mechanism can be utilized to treat bone metastasis. Utilizing a bone metastatic breast cancer mouse model, we discovered that autophagy is enhanced by Runx2. We demonstrated that Runx2 facilitates acetylation of microtubules (MTs), a critical step in trafficking of autophagosomes. Previously, we reported that Runx2 promotes metastasis of breast cancer cells. Based on these findings, our central hypothesis is that metastatic breast cancer cells survive in the bone microenvironment via Runx2-dependent autophagy. To test this hypothesis we propose the following Aims: 1) Define the mechanism of Runx2-mediated microtubule acetylation during autophagy. We will examine the impact of Runx2-mediated acetylation of α-tubulin subunits of MTs on autophagy. We will determine the interaction among Runx2 and co-factors regulating acetylation of MTs. For this, we will use bone metastatic breast cancer cells expressing altered levels of Runx2 or HDAC6. 2) Determine the impact of Runx2-mediated autophagy on bone metastasis. We will examine the Runx2-mediated autophagy function by altering Runx2 levels in combination with (i) inhibition of HDAC6 activity, (ii) expression of an acetylation-deficient mutant of α- tubulin subunit of MTs, and (iii) treatment with a pharmacologic inhibitor of autophagy in xenograft and syngeneic tumor mouse models of bone metastasis. Our proposed studies will reveal novel survival mechanisms of bone metastatic breast cancer cells and will identify critically needed targets for treatment of metastatic bone disease.

抽象的： 我们建议的具体目标是了解与Runt相关因子-2（Runx2）介导的机制 乳腺癌骨转移的自噬。 癌症的癌症。 每年。最近的研究表明，转移性癌细胞会诱发应力条件。 自噬是细胞质成分高度调节的机制，在这里被溶酶体降解 对于饥饿期间的细胞存活。 相应地，骨转移仍然很差。 自噬并了解如何利用这种调节机制来治疗骨转移 骨转移性乳腺癌小鼠模型，我们发现自噬通过Runx2增强 证明Runx2促进了微管（MTS），这是贩运的关键步骤 自噬体以前，我们报道了Runx2促进了基于乳腺癌细胞的转移 这些发现，我们的中心假设是转移性乳腺癌细胞在骨骼中存活 通过runx2依赖性自噬来检验该假设的微环境我们提出以下AMS：1） 定义runx2介导的微管乙酰化的机制，我们将检查一下自噬。 Runx2介导的MTα-微管蛋白亚基对自噬的影响。 Runx2与调节MT的乙酰化的辅助因素之间的相互作用。 表达Runx2或HDAC6水平的乳腺癌细胞确定Runx2介导的影响 自噬在骨转移上。 水平与（i）抑制HDAC6活性相结合，（ii）表达乙酰化α-的表达 MTS的微管蛋白亚基，以及（III）用自噬的药理学抑制剂在纳学 骨转移的合成性肿瘤小鼠模型。 骨转移性乳腺癌细胞的机制，并将确定对治疗的批判性目标 转移性骨病。