Chemical Genetic Dissection of Aurora A in Promoting EMT and Stem Cells Phenotype

Aurora A 促进 EMT 和干细胞表型的化学遗传学解析

• 批准号: 8634747
• 负责人: Kavita Shah
• 金额: $ 7.47万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634747
• 关键词: Adverse effects; Apoptosis; Biological Markers; Cancer Patient; Cell Cycle; Cell Death; Cells; Clinical; Clinical Trials; Data; Development; Diagnosis; Diagnostic; Diffuse; Disease Management; Dissection; Dose; Drug Targeting; Drug resistance; Effectiveness; Enzymes; Epithelial Cells; Exhibits; Feedback; G2 Phase; Genetic Screening; Goals; Human; Light; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mitosis; Mitotic; Molecular; Neoplasm Metastasis; Normal Cell; Nuclear; Nuclear Proteins; Oncogenic; Oncologist; Outcome; Pancreas; Pathway interactions; Phase; Phase II Clinical Trials; Phenotype; Phosphorylation; Plant Roots; Play; Prognostic Marker; Property; Proteins; Radiation therapy; Recurrence; Refractory; Research; Resistance; Role; Sampling; Signal Transduction; Solid Neoplasm; Stem cells; Taxane Compound; Testing; Tissues; Toxic effect; Treatment Efficacy; Tumorigenicity; Up-Regulation; Validation; Work; aurora-A kinase; base; cancer cell; cancer stem cell; cell type; chemical genetics; chemotherapeutic agent; effective therapy; epithelial to mesenchymal transition; human STK6 protein; in vivo; inhibitor/antagonist; innovation; novel; overexpression; pancreatic cancer cells; pancreatic neoplasm; prevent; prognostic; public health relevance; response; self-renewal; taxane; therapeutic target; tool; transcription factor; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is extremely lethal. Early metastasis prior to diagnosis, tumor recurrence and resistance towards current chemo-radiation therapies are common among PC patients. Recent evidence indicates that the acquisition of epithelial-to-mesenchymal transition (EMT) and induction of cancer stem cell (CSC) phenotypes in PC tumors are important underlying causes for these occurrences. However, the mechanisms leading to EMT and CSC phenotypes remain unclear. This information is critical for the discovery of novel targeted therapies for the treatment of PC that offer superior outcome. The long term goal is to identify therapeutically effective drug targets in PC. Our recent unpublished data have uncovered a critical role of Aurora A (AA) kinase in promoting EMT and CSC in PC. AA is upregulated in PC and contributes significantly to tumorigenesis and metastasis; however, the molecular mechanisms remain unknown. Using an innovative chemical genetic screen, FOXM1 transcription factor was identified as a direct target of AA in highly malignant AsPC1 cells. AA directly phosphorylates FOXM1 at S361 stabilizing its levels. In turn, FOXM1 also stabilizes AA levels, thereby triggering a reciprocal positive feedback loop. FOXM1 upregulation is known to promote EMT and CSC phenotypes in PC cells. The objective in this proposal is to determine the contribution of FOXM1 as a critical effector of AA by which it promotes EMT and CSC phenotype in PC tumors. The central hypothesis is that AA and FOXM1 are potential drug targets which promote aggressive oncogenic pathways in PC synergistically. This hypothesis will be tested by pursuing three specific aims: 1) Determine a potential role of AA in promoting EMT and CSC in PC cells. 2) Determine the consequences of AA-mediated phosphorylation of FOXM1 on various oncogenic pathways in PC cells. 3) Determine AA and FOXM1 levels in tandem in human clinical samples and their correlation with clinical outcomes. The approach is innovative because the central hypothesis was formulated based on a novel AA substrate, FOXM1, discovered using a powerful chemical genetic approach. No cancer-specific substrate of AA has been identified in PC. AA has not been linked to CSC or EMT to date. Furthermore, FOXM1 or AA levels have not been analyzed in tandem in human PC tissues. The proposed research is significant because validation of FOXM1 as an AA substrate will provide a potent tool to inhibit FOXM1 deregulation in metastatic PC. Correlation of AA and FOXM1 levels with divergent clinical outcomes are expected to reveal potential prognostic and diagnostic biomarkers for PC. The positive impact of our work will be the validation of AA as a potential drug target for treating/preventing EMT, CSC and chemoresistance, either alone or in combination with FOXM1 inhibitors.

描述（由申请人提供）：胰腺癌（PC）是非常致命的。诊断前的早期转移，肿瘤复发和对当前化疗放疗的抵抗在PC患者中很常见。最近的证据表明，在PC肿瘤中获得上皮-间质转化（EMT）和诱导癌症干细胞（CSC）表型是这些发生的重要潜在原因。然而，导致EMT和CSC表型的机制尚不清楚。这一信息对于发现治疗前列腺癌的新型靶向疗法具有重要意义，可以提供更好的治疗效果。长期目标是确定治疗PC有效的药物靶点。我们最近未发表的数据揭示了Aurora a （AA）激酶在促进PC的EMT和CSC中的关键作用。AA在PC中表达上调，在肿瘤发生和转移中起重要作用；然而，分子机制尚不清楚。利用创新的化学遗传筛选，FOXM1转录因子被确定为高度恶性AsPC1细胞中AA的直接靶点。AA直接磷酸化FOXM1的S361位点，稳定其水平。反过来，FOXM1也稳定了AA水平，从而触发了一个相互的正反馈循环。已知FOXM1上调可促进PC细胞的EMT和CSC表型。本研究的目的是确定FOXM1作为AA的关键效应因子在PC肿瘤中促进EMT和CSC表型的作用。中心假设是AA和FOXM1是潜在的药物靶点，它们协同促进PC的侵袭性致癌途径。这一假设将通过追求三个具体目标来验证：1)确定AA在促进PC细胞EMT和CSC中的潜在作用。2)确定aa介导的FOXM1磷酸化对PC细胞各种致癌途径的影响。3)确定人类临床样本中AA和FOXM1的串联表达及其与临床结果的相关性。这种方法是创新的，因为中心假设是基于一种新的AA底物FOXM1， FOXM1是用一种强大的化学遗传方法发现的。在PC中没有发现特异性的AA底物。到目前为止，AA还没有与CSC或EMT联系起来。此外，FOXM1或AA水平尚未在人PC组织中串联分析。该研究具有重要意义，因为FOXM1作为AA底物的验证将提供一种有效的工具来抑制转移性PC中FOXM1的失调。AA和FOXM1水平与不同临床结果的相关性有望揭示PC的潜在预后和诊断生物标志物。我们工作的积极影响将是验证AA作为治疗/预防EMT、CSC和化疗耐药的潜在药物靶点，无论是单独使用还是与FOXM1抑制剂联合使用。

项目成果

Design, synthesis and in vitro cytotoxicity studies of novel β-carbolinium bromides.

• DOI: 10.1016/j.bmcl.2017.02.010
• 发表时间: 2017-03-15
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Venkataramana Reddy PO;Mishra S;Tantak MP;Nikhil K;Sadana R;Shah K;Kumar D
• 通讯作者: Kumar D

Synthesis and investigations into the anticancer and antibacterial activity studies of β-carboline chalcones and their bromide salts.

• DOI: 10.1016/j.bmcl.2018.03.033
• 发表时间: 2018-05-01
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Venkataramana Reddy PO;Hridhay M;Nikhil K;Khan S;Jha PN;Shah K;Kumar D
• 通讯作者: Kumar D

Phosphorylation-dependent regulation of ALDH1A1 by Aurora kinase A: insights on their synergistic relationship in pancreatic cancer.

• DOI: 10.1186/s12915-016-0335-5
• 发表时间: 2017-02-13
• 期刊: BMC biology
• 影响因子: 5.4
• 作者: Wang J;Nikhil K;Viccaro K;Chang L;White J;Shah K
• 通讯作者: Shah K

2-(3'-Indolyl)-N-arylthiazole-4-carboxamides: Synthesis and evaluation of antibacterial and anticancer activities.

2-(3-吲哚基)-N-芳基噻唑-4-甲酰胺：抗菌和抗癌活性的合成和评价。

• DOI: 10.1016/j.bmcl.2015.07.105
• 发表时间: 2015
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Tantak,MukundP;Wang,Jing;Singh,RajnishPrakash;Kumar,Anil;Shah,Kavita;Kumar,Dalip
• 通讯作者: Kumar,Dalip

Sequential one-pot synthesis of bis(indolyl)glyoxylamides: Evaluation of antibacterial and anticancer activities.

双(吲哚基)乙醛酰胺的连续一锅合成：抗菌和抗癌活性评价。

• DOI: 10.1016/j.bmcl.2016.04.080
• 发表时间: 2016
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Tantak,MukundP;Gupta,Vishakha;Nikhil,Kumar;Arun,V;Singh,RajnishPrakash;Jha,PrabhatNath;Shah,Kavita;Kumar,Dalip
• 通讯作者: Kumar,Dalip