AMPK Regulation of Microtubule Dynamics in Breast Cancer Metastasis

AMPK 对乳腺癌转移中微管动力学的调节

基本信息

批准号：
9330781
负责人：
Kristi Chakrabarti Briggs
金额：
$ 3.74万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330781
关键词：
Adenosine Monophosphate Adverse effects Affect Apoptotic Binding Proteins Biological Markers Blood Blood Circulation Blood Vessels Blood capillaries Breast Cancer Cell Breast Cancer Patient Breast Cancer therapy Breast cancer metastasis C-terminal Cause of Death Cell Death Cell Polarity Cell membrane Cell-Matrix Junction Cells Cellular biology Chemotherapy-Oncologic Procedure Clinical Clinical Trials Clip Confocal Microscopy Cytoskeletal Proteins Detection Devices Disease Distant Epithelial Epithelial Cells Frequencies Glutamic Acid Goals Half-Life Homeostasis In Vitro Invaded Mammary Neoplasms Measures Membrane Metabolic Metastatic breast cancer Metastatic to Microfluidics Microtubule Polymerization Microtubule Stabilization Microtubules Molecular Mutation Neoplasm Circulating Cells Neoplasm Metastasis Organ Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phosphorylation Plus End of the Microtubule Post-Translational Protein Processing Primary Neoplasm Process Protein Kinase Proteins Publishing Regulation Risk Role Sampling Serine Site Stream Structure Testing Therapeutic Tissue Microarray Tubulin Tumor Tissue Tumor stage Tumor-Derived Tyrosine Xenograft procedure alpha Tubulin base cancer cell capillary cytotoxic detection of nutrient in vivo malignant breast neoplasm neoplastic cell new therapeutic target novel novel therapeutics outcome forecast prevent public health relevance response success targeted cancer therapy taxane therapeutic target tumor tumor progression whole animal imaging

项目摘要

DESCRIPTION (provided by applicant): Primary breast tumors can shed millions of cells into the blood stream, known as circulating tumor cells (CTCs), at early stages of tumor progression. CTCs are able to survive in the circulation and arrest at distant sites to form metastatic disease. The presence of CTCs in a patient with breast cancer is associated with poor prognosis and increased risk of metastasis. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) has anti-tumor activity in breast cancer and is currently being evaluated in clinical trials as a target for breast cancer therapy. However, the role of AMPK in breast cancer metastasis is largely unknown. Most studies have focused on the function of AMPK as a cellular metabolic regulator, but AMPK has numerous other roles including maintaining epithelial cell polarity and regulating cytoskeletal proteins. Disseminated epithelial tumor cells use tubulin-based structures known as microtentacles to adhere to blood vessel walls in order to survive in the circulation and arrest in the capillaries of distant organs. There is a higher frequency of microtentacles in metastatic breast cancer cells, and microtentacles are enriched with a stable, detyrosinated form of a- tubulin. AMPK can phosphorylate the microtubule plus-end binding protein, clip-170, which results in decreased microtubule stability in normal epithelial cells. In this study, we will establish the role of AMPK in stabilizing microtubules in breast cancer. Furthermore, we will investigate the effects of clip-170 phosphorylation on microtubule stability and the metastatic efficiency of detached breast tumor cells. This study will test the hypothesis that AMPK activation decreases microtubule stability, resulting in decreased CTC attachment. We will test this hypothesis in the following specific aims: 1) Determine the extent of AMPK regulation of microtubule stability and microtentacle formation. 2) Define how AMPK phosphorylation of clip- 170 affects CTC attachment and metastasis. Current chemotherapeutics used in breast cancer therapy that target microtubules can enhance microtentacle formation and increase CTC re- attachment. Clip-170 provides a novel therapeutic target for microtubule stability that may reduce the metastatic success of CTCs or act as a biomarker for AMPK therapy. Completion of this study will help determine the therapeutic potential of AMPK-directed drugs to decrease the attachment of CTCs to blood vessels. Therefore, we can take advantage of the existing and developing pharmacological AMPK activators to decrease CTC metastasis and increase survival of patients with breast cancer.

描述（由申请人提供）：原发性乳腺肿瘤可以将数百万个细胞（称为循环肿瘤细胞（CTC））释放到血流中，在肿瘤进展的早期阶段，CTC 能够在循环中存活并滞留在远处部位。形成转移性疾病。乳腺癌患者中 CTC 的存在与预后不良和转移风险增加有关。单磷酸腺苷 (AMP) 激活蛋白激酶 (AMPK) 在乳腺癌中具有抗肿瘤活性，目前正在临床试验中进行评估。作为乳腺癌治疗的靶标然而，大多数研究都集中在 AMPK 作为细胞代谢调节剂的功能上，但 AMPK 还具有许多其他作用，包括维持上皮细胞极性和调节。播散性上皮肿瘤细胞使用基于微管蛋白的结构（称为微触手）粘附在血管壁上，以便在循环中存活并滞留在远处器官的毛细血管中。转移性乳腺癌细胞中的微触手富含稳定的去酪氨酸形式的 a-微管蛋白，AMPK 可以磷酸化微管正端结合蛋白 Clip-170，从而导致正常上皮细胞中的微管稳定性降低。学习，我们会确定 AMPK 在稳定乳腺癌微管中的作用此外，我们将研究 Clip-170 磷酸化对微管稳定性和分离乳腺肿瘤细胞转移效率的影响。我们将在以下具体目标中检验这一假设：1) 确定 AMPK 对微管稳定性和微触手形成的调节程度。 Clip-170 的 AMPK 磷酸化影响 CTC 附着和转移，目前用于乳腺癌治疗的靶向微管的化疗药物可以增强微触手形成并增加 CTC 重新附着，从而为可能降低转移成功率的微管稳定性提供了新的治疗靶点。完成这项研究将有助于确定 AMPK 导向药物减少 CTC 与血液附着的治疗潜力。因此，我们可以利用现有和正在开发的药理学 AMPK 激活剂来减少 CTC 转移并提高乳腺癌患者的生存率。