COX-2 and p53 interactions and cancer prevention

COX-2 和 p53 相互作用与癌症预防

• 批准号: 6804993
• 负责人: M. SAEED SHEIKH
• 金额: $ 7.6万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804993
• 关键词: apoptosis; cancer prevention; chemoprevention; enzyme inhibitors; gene expression; gene induction /repression; neoplastic growth; p53 gene /protein; polymerase chain reaction; prostaglandin endoperoxide synthase; protein protein interaction; tetracyclines; transfection /expression vector

DESCRIPTION (provided by applicant): Cyclooxygenase 2 (COX-2) is overexpressed in human malignancies and is a promising target to develop novel chemopreventive strategies. Clinical trials are currently in progress to investigate the efficacy of COX-2 selective non-steroidal anti-inflammatory drugs in the prevention of various types of cancers. However, much remains to be elucidated as to how COX-2-selective agents mediate chemopreventive effects. A better understanding of the molecular mechanisms that regulate COX-2 expression will certainly facilitate the development of more effective and less toxic cancer-preventive strategies. In this regard, the tumor suppressor p53 has been found to promote upregulation of COX-2 mRNA and protein levels. COX-2 has been implicated in positive growth regulation and tumorigenesis while tumor suppressor p53 is a negative regulator of growth. Thus, p53-dependent upregulation of COX-2 appears rather incongruous. It has been proposed that p53-dependent COX-2 upregulation could be a mechanism to abate the apoptotic effects of p53. The work proposed in this two-year pilot study will directly evaluate the hypothesis that p53-dependent COX-2 upregulation is a compensatory response that serves to abate the p53-induced apoptosis. In order to accomplish our goals, we have proposed two specific aims. In Specific Aim 1, we will investigate whether COX-2 negatively affects the function of wild type p53. We will establish tetracycline or doxycycline-inducible COX-2 and p53 double-inducible cells to investigate whether COX-2 negatively affects the function of wild type p53. By using the double-inducible cells that would exhibit simultaneous induction of COX-2 and p53, we will ensure that higher levels of COX-2 are available from the beginning. Thus, if COX-2 negatively affects the function of wild type p53 then it will be instantly available to mediate its effect on p53. In Specific Aim 2, we will abrogate COX-2 expression via RNA interference approach to test the effect of COX-2 deficiency on p53 functions including p53-induced apoptosis. Thus, investigating the molecular mechanisms that control the interplay between COX-2 and p53 activities is relevant and the outcome, if successful, would improve our understanding of the malignant development and progression to further the progress in developing novel, more effective and less toxic cancer-preventive strategies.

描述（由申请人提供）： 环氧合酶2（考克斯-2）在人类恶性肿瘤中过表达，是一个有希望的开发新的化学预防策略的目标。目前正在进行临床试验以研究考克斯-2选择性非甾体抗炎药在预防各种类型癌症中的功效。然而，关于考克斯-2-选择性药物如何介导化学预防作用仍有许多问题有待阐明。更好地了解调控考克斯-2表达的分子机制，必将有助于开发更有效、毒性更小的癌症预防策略。在这方面，已经发现肿瘤抑制因子p53促进考克斯-2 mRNA和蛋白水平的上调。考克斯-2与正性生长调节和肿瘤发生有关，而肿瘤抑制因子p53是生长的负性调节因子。因此，考克斯-2的p53依赖性上调似乎相当不协调。已经提出p53依赖性考克斯-2上调可能是减弱p53的凋亡作用的机制。这项为期两年的初步研究将直接评估p53依赖性考克斯-2上调是一种代偿性反应，可减轻p53诱导的细胞凋亡。为了实现我们的目标，我们提出了两个具体目标。在具体目标1中，我们将研究考克斯-2是否对野生型p53的功能产生负面影响。我们将建立四环素或多西环素诱导的考克斯-2和p53双诱导细胞，以研究考克斯-2是否对野生型p53的功能产生负面影响。通过使用同时诱导考克斯-2和p53的双重诱导细胞，我们将确保从一开始就可获得更高水平的考克斯-2。因此，如果考克斯-2负面影响野生型p53的功能，那么它将立即可用于介导其对p53的作用。在具体目标2中，我们将通过RNA干扰方法消除考克斯-2表达，以测试考克斯-2缺陷对p53功能包括p53诱导的细胞凋亡的影响。因此，研究控制考克斯-2和p53活性之间相互作用的分子机制是相关的，如果成功的话，将提高我们对恶性发展和进展的理解，以进一步发展新的、更有效的和毒性更小的癌症预防策略。