Target MKP-1 for Therapy-Resistant Breast Cancer Stem Cells

治疗耐药乳腺癌干细胞的靶点 MKP-1

基本信息

批准号：
8450278
负责人：
Jian Jian Li
金额：
$ 35.44万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-08 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450278
关键词：
Activation Analysis Affect Antineoplastic Agents Apoptosis Apoptotic Attenuated Biological Assay Breast Cancer Cell CD44 gene Cancer Patient Cancer cell line Cell Line Cell Survival Cells Clinical Collaborations Cultured Cells DUSP1 gene Data Doctor of Medicine Doctor of Philosophy ERBB2 gene Epidermal Growth Factor Receptor Event Failure Genetic Transcription Growth Growth Factor Receptors Human Inhibition of Apoptosis Life Lung MAPK phosphatase MAPK8 gene Malignant Neoplasms Mediating Mediator of activation protein Microscopy Mitochondria Molecular Molecular Chaperones Mus NF-kappa B Neoplasm Metastasis Oxidation-Reduction Pathology Pathway interactions Phenotype Phosphorylation Primary Neoplasm Protein Dephosphorylation Radiation Radiation Tolerance Radioresistance Recurrence Recurrent tumor Resistance Role Sampling Signal Transduction Stem cells Testing Tumorigenicity aggressive therapy cancer cell cancer stem cell cancer therapy improved insight irradiation malignant breast neoplasm matrigel new therapeutic target next generation overexpression programs public health relevance response self-renewal stress-activated protein kinase 1 therapy resistant trafficking tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Tumor resistance, recurrence and metastasis are the primary causes of the failure of cancer treatments. Although extensively studied, the fundamental mechanism underlying the aggressive therapy-resistant tumor phenotype remains to be a major challenge in improving overall cancer cure rate. NF-kB-mediated pro-survival networks are shown to be important mediators of increased survival and radioresistance in breast cancer cells that survive a long- term fractionated irradiation. Recent new evidence further indicate that NF-kB-induces the expression of MAPK phosphatase 1 (MKP1) that is capable of inhibiting apoptosis by attenuating mitochondria-mediated apoptosis in radiation-resistant breast cancer cells. Data provided in this proposal indicate that MKP1 locates in the mitochondria and radiation enhances its mitochondrial influx resulting in the reduction of its substrate JNK phosphorylation, a key event in mitochondria-mediated apoptosis. In addition, breast cancer + -/low stem cells (CSCs with CD44 /CD24) have been identified to be radioresistant and enriched in the surviving fraction of breast cancer cells irradiated with fractionated irradiation. In this study, we propose to elucidate the signaling network of MKP1-mediated anti- mitochondrial apoptosis response in radiation-derived radioresistant breast cancer cell lines. We will investigate whether MKP1-mediated anti-apoptotic response is specifically activated in breast cancer stem cells that are believed to be radioresistant and enriched in the recurrent and metastatic tumor of cancer patients. The hypothesis to be tested is that MKP1- mitochondrial translocation inhibits mitochondrial JNK activity and mitochondria-dependent apoptosis in radioresistant breast CSCs. There are Three Specific Aims: 1, Test whether mitochondrial translocation of MKP1 is responsible for tumor radioresistance; 2, Elucidate the molecular mechanisms upstream of MKP1 activation leading to the inhibition of apoptosis; and 3, Detect ERK/MKP1-mediated pro-survival response in radioresistant + -/low CD44 /CD24 breast cancer stem cells in recurrent/metastatic tumors.

描述（申请人提供）：肿瘤耐药、复发和转移是癌症治疗失败的主要原因。尽管进行了广泛的研究，但侵袭性治疗耐药肿瘤表型的基本机制仍然是提高癌症总体治愈率的主要挑战。 NF-kB 介导的促生存网络被证明是在长期分段照射后存活的乳腺癌细胞中提高存活率和放射抗性的重要介质。最近的新证据进一步表明，NF-kB 诱导 MAPK 磷酸酶 1 (MKP1) 的表达，该酶能够通过减弱抗辐射乳腺癌细胞中线粒体介导的细胞凋亡来抑制细胞凋亡。该提案中提供的数据表明，MKP1 位于线粒体中，辐射增强了其线粒体流入，导致其底物 JNK 磷酸化减少，这是线粒体介导的细胞凋亡的关键事件。此外，乳腺癌+-/低干细胞（具有CD44/CD24的CSC）已被鉴定为具有放射抗性，并且在经分段照射的乳腺癌细胞的存活部分中富集。在这项研究中，我们拟阐明放射源抗辐射乳腺癌细胞系中 MKP1 介导的抗线粒体凋亡反应的信号网络。我们将研究 MKP1 介导的抗凋亡反应是否在乳腺癌干细胞中被特异性激活，这些干细胞被认为具有放射抗性，并且在癌症患者的复发性和转移性肿瘤中富集。要测试的假设是 MKP1-线粒体易位抑制放射抗性乳腺 CSC 中的线粒体 JNK 活性和线粒体依赖性细胞凋亡。具体目标有3个： 1、检测MKP1的线粒体易位是否与肿瘤放射抗性有关； 2、阐明MKP1激活上游抑制细胞凋亡的分子机制； 3、检测复发性/转移性肿瘤中放射抗性+-/低CD44/CD24乳腺癌干细胞中ERK/MKP1介导的促生存反应。