NF-kB targets in the chemoresistance of GI malignancies

NF-kB 是胃肠道恶性肿瘤化疗耐药的靶标

基本信息

批准号：
6775296
负责人：
HONG JIN KIM
金额：
$ 13.02万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-21 至 2009-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Advanced gastrointestinal (GI) solid tumors, in particular adenocarcinoma of the pancreas, remain largely resistant to current standard chemotherapeutic agents. Inducible chemoresistance is attributed to the ability of neoplastic cells to overcome apoptosis, or programmed cell death. Importantly, the activation of the transcription factor NF-kappaB has been shown to diminish the genotoxic effects of current anticancer therapies, in a variety of malignancies. NF-kappaB is activated in response to numerous factors (TNFalpha, radiation, chemotherapy), and is regulated primarily through a complex interaction with an inhibitor protein, IkappaB [11]. In response to these factors, IkappaB is phosphorylated resulting in rapid ubiquitination and proteolysis by the proteasome; phosphorylation of IkappaB involves two key catalytic subunits of IkappaB kinase (IKK), IKKalphaand IKKbeta. Ultimately, NF-kappaB is involved in the suppression of apoptosis, control of proliferation, suppression of cellular differentiation, and the induction of cell migration. Recently, our laboratory established that inducible activation of NF-kappaB in a human colon cancer cell line diminished the apoptotic response to chemotherapy (CPT-11) and irradiation [12]. Inhibition of NF-kappaB using IkappaB expression or a proteasome inhibitor (PS-341) led to enhanced tumoricidal response to chemotherapy [13]; these studies have resulted in ongoing clinical Phase I trials. A more specific inhibitor of NF-kappaB, an IKK inhibitor (PS-1145), may lead to improved combinational strategies, and contribute to the further understanding of NF-kappaB signaling in response to chemotherapy. The NF-kappaB-regulated genes involved in chemoresistance are poorly characterized, and activation of NF-kappaB in pancreatic cancer is in the earliest stages of investigation. Preliminary data indicate that NF-kappaB is constitutively expressed in pancreatic cancer cell lines, and activated in response to standard chemotherapy (5-fluorouracil and gemcitabine). Whether NF-kappaB inhibition represents a novel target-directed strategy to enhance cytotoxicity of chemotherapy agents in pancreatic cancer remains to be seen. Furthermore, NF-kappaB may regulate other signaling mechanisms which impact on the efficacy of cancer therapy. NF-kappaB negatively regulates Jun N-terminal kinase (JNK) activation and TNF-induced JNK activity appears to be anti-apoptotic when NF-kappaB is suppressed. The major goals of this proposal are to characterize the role of NF-kappaB in the chemoresistance of pancreatic cancer, with an emphasis on identifying signaling pathways regulated by NF-kappaB to block cancer therapy.

描述（由申请人提供）：晚期胃肠道（GI）实体瘤，特别是胰腺腺癌，在很大程度上对当前标准化学治疗剂具有抗性。诱导化学抗性归因于肿瘤细胞克服凋亡或编程细胞死亡的能力。重要的是，在多种恶性肿瘤中，转录因子NF-kappab的激活已被证明会减少当前抗癌疗法的遗传毒性作用。 NF-kappab是针对许多因素（TNFalpha，放射，化学疗法）激活的，并且主要通过与抑制剂蛋白Ikappab的复杂相互作用来调节[11]。响应这些因素，iKappab是磷酸化的，导致蛋白酶体的快速泛素化和蛋白水解。 Ikappab的磷酸化涉及Ikkalphaand Ikkbeta的Ikappab激酶（IKK）的两个关键催化亚基。最终，NF-kappab参与抑制细胞凋亡，控制增殖，抑制细胞分化以及细胞迁移的诱导。最近，我们的实验室确定，在人类结肠癌细胞系中NF-kappab的诱导性激活减少了对化学疗法（CPT-11）和辐射的凋亡反应[12]。使用IKAPPAB表达或蛋白酶体抑制剂（PS-341）抑制NF-kappab导致对化学疗法的肿瘤反应增强[13]；这些研究导致了I期持续的I期试验。 IKK抑制剂（PS-1145）的NF-kappab的更特异性抑制剂可能会改善组合策略，并有助于进一步理解NF-kappab信号，以响应化学疗法。参与化学耐药性的NF-kappab调节的基因的表征很差，胰腺癌中NF-kappab的激活是最早的研究阶段。初步数据表明，NF-kappab在胰腺癌细胞系中组成型表达，并根据标准化学疗法（5-氟尿嘧啶和吉西他滨）而激活。 NF-kappab抑制是否代表了一种新型的目标指导策略，以增强胰腺癌化学疗法的细胞毒性毒性。此外，NF-kappab可能会调节其他信号机制，从而影响癌症治疗的功效。 NF-kappab对NF-kappab抑制时，负调控Jun N末端激酶（JNK）激活和TNF诱导的JNK活性似乎是抗凋亡。该提案的主要目标是表征NF-kappab在胰腺癌化学上的作用，重点是鉴定NF-kappab调节以阻止癌症治疗的信号传导途径。