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

• 批准号: 8634735
• 负责人: Jian Jian Li
• 金额: $ 36.13万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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/8634735
• 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

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。尽管研究广泛，但侵袭性耐药肿瘤表型的基本机制仍然是提高整体癌症治愈率的主要挑战。nf - kb介导的促生存网络被证明是长期分次照射后乳腺癌细胞存活和放射耐药增加的重要介质。最近的新证据进一步表明，nf - kb诱导MAPK磷酸酶1 （MKP1）的表达，MKP1能够通过减弱线粒体介导的辐射耐药乳腺癌细胞凋亡来抑制细胞凋亡。本研究提供的数据表明，MKP1位于线粒体中，辐射增强其线粒体内流，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+ -/低水平干细胞（具有CD44 /CD24的CSCs）已被鉴定为具有放射抗性，并且在经过分次辐照的乳腺癌细胞存活部分中富集。在这项研究中，我们提出阐明mkp1介导的辐射源性放射耐药乳腺癌细胞系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，这些干细胞被认为在癌症患者的复发和转移肿瘤中具有放射耐药和富集。待验证的假设是MKP1-线粒体易位抑制放射耐药乳腺CSCs中线粒体JNK活性和线粒体依赖性凋亡。具体目的有三个：1、检测MKP1的线粒体易位是否与肿瘤放射耐药有关；2、阐明MKP1激活上游导致细胞凋亡抑制的分子机制；3、检测复发/转移性肿瘤中放射耐药+ -/低CD44 /CD24乳腺癌干细胞中ERK/ mkp1介导的促生存反应。