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

描述（由申请人提供）：肿瘤耐药性、复发和转移是癌症治疗失败的主要原因。虽然广泛研究，但侵袭性治疗抗性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介导的促存活网络被证明是在长期分次照射后存活的乳腺癌细胞中增加的存活和放射抗性的重要介质。最近的新证据进一步表明，NF-κ B诱导MAPK磷酸酶1（MKP 1）的表达，能够通过减弱辐射抗性乳腺癌细胞中的细胞凋亡来抑制细胞凋亡。该提案中提供的数据表明，MKP 1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，这是细胞凋亡中的关键事件。此外，乳腺癌+/低干细胞（具有CD 44/CD 24的CSC）已被鉴定为具有放射抗性，并富集在用分次照射照射的乳腺癌细胞的存活部分中。在本研究中，我们拟阐明MKP 1介导的抗线粒体凋亡反应在放射源性放射抵抗乳腺癌细胞系中的信号网络。我们将研究MKP 1介导的抗凋亡反应是否在乳腺癌干细胞中特异性激活，这些干细胞被认为是放射抗性的，并且在癌症患者的复发性和转移性肿瘤中富集。待检验的假设是MKP 1-线粒体易位抑制放射抗性乳腺CSC中的线粒体JNK活性和JNK α依赖性凋亡。有三个具体目标：1、检测MKP 1的线粒体易位是否是肿瘤放射抗性的原因; 2、阐明MKP 1激活上游导致细胞凋亡抑制的分子机制; 3、检测复发/转移性肿瘤中放射抗性+/低CD 44/CD 24乳腺癌干细胞中ERK/MKP 1介导的促存活反应。

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.