Tumor Suppression Through Oxidized Glycerophosphocholines

通过氧化甘油磷酸胆碱抑制肿瘤

• 批准号: 7708753
• 负责人: RAYMOND L KONGER
• 金额: $ 23.1万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7708753
• 关键词: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Acetates; Acetylcysteine; Agonist; Antineoplastic Agents; Antioxidants; Applications Grants; Ascorbic Acid; Back; Benzoyl Peroxide; Biochemical; Biological; Biological Assay; Chemicals; Chemopreventive Agent; Cutaneous; Development; Disease; Epidermis; Exhibits; Figs - dietary; Free Radicals; Genes; Genotype; Goals; Growth; Hormones; Human; Hyperplasia; Knock-out; Knockout Mice; Lead; Ligands; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Mus; Neoplasms; Oxidative Stress; PPAR gamma; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Play; Polyunsaturated Fatty Acids; Predisposition; Production; Property; Protocols documentation; Reactive Oxygen Species; Role; Skin; Specificity; Staging; Stress; System; Testing; Therapeutic; Time; Topical application; Tumor Promoters; Tumor Promotion; Tumor Suppression; Wild Type Mouse; antioxidant therapy; base; biological adaptation to stress; carcinogenesis; design; environmental chemical; in vivo; insight; mouse model; neoplastic; oxidized lipid; phorbol-12-myristate; platelet activating factor receptor; pre-clinical; protective effect; public health relevance; receptor; response; tumor

DESCRIPTION (provided by applicant): Oxidative stress has long been known to be an important trigger for neoplastic development. The importance of oxidative stress in carcinogenesis is seen in the ability of chemical and environmental tumor promoters to induce the production of reactive oxygen species. Not surprisingly, a number of antioxidants have been examined for potential chemopreventive activity. While there is strong pre-clinical and epidemiologic evidence to support the idea that antioxidants have antineoplastic properties, more recent human studies have shown mixed results. If successful, the studies proposed in this grant application will provide key insights into cellular responses to oxidative stress, particularly in regards to tumor promotion. Importantly, these insights may lead to better chemopreventive approaches to neoplastic development. Studies by our group and others have indicated that oxidative stress results in the production of oxidized glycerophosphocholines (ox-GPC) that act as agonists for the platelet-activating factor receptor (PAF-R) and the peroxisome proliferator activated receptor gamma (PPAR?) systems. Moreover, we and others provide evidence that the PAF-R and PPAR? act to suppress the tumor promoter-induced hyperproliferative response as well as long-term cutaneous neoplasia. We hypothesize that ox-GPCs with PAF-R and PPAR? agonist activity have evolved as a cellular defense against tumor promoter-induced neoplastic development. They do this by acting as a brake on tumor promoter- induced hyperplastic responses and subsequent tumor development. We further propose that antioxidants suppress this protective response by blocking the production of ox-GPCs; thus, we expect that adding back these ox-GPCs or specific agonists for the PAF-R and/or PPAR? would augment the chemopreventive activity of antioxidant therapy. Three specific aims are designed to test these hypotheses. 1.) We will first verify that two different chemical tumor promoters induce the production of these ox-GPCs in mouse epidermis. We will then verify in mouse epidermis that topically applied ox-GPCs, as well as defined PAF-R and PPAR? agonists, are capable of activating the PAF-R and PPAR?. The specificity of these responses will be verified in gene knockout mice lacking the PAF-R (PAF-R(-/-)) or epidermal PPAR? (PPAR?(-/-)). 2.) We will next demonstrate that the PAF-R and PPAR? suppress tumor-promoter induced growth using these knockout mouse models. We will then verify that adding back exogenous ox-GPCs, a PAF-R agonist, or a PPAR? agonist all act to augment the ability of antioxidants to block tumor promoter-induced hyperproliferative responses. 3.) Finally, using normal mice as well as these knockout mice, we will directly determine whether the chemopreventive activity of antioxidants can be boosted by adding back exogenous ox-GPCs or specific PAF-R and/or PPAR? agonists. These studies are part of my long-term goals to define the receptor based mechanisms through which lipid hormones are involved in neoplastic development. PUBLIC HEALTH RELEVANCE: Two common features of all tumor promoters are the production reactive oxygen species and the induction of a sustained hyperproliferative response in the epidermis. Recent studies by our group have demonstrated that reactive oxygen species induce the production of oxidized glycerophosphocholines (ox-GPC) that can act as agonists for the growth inhibitory platelet-activating factor receptor (PAF-R) and peroxisome proliferator activated receptor gamma (PPAR?) systems. The proposed studies will determine whether tumor promoters induce ox-GPCs that serve a protective function in neoplastic development by activating growth-inhibitory PAF-R and/or PPAR?.

描述（由申请人提供）：氧化应激长期以来一直被认为是肿瘤发展的重要触发因素。氧化应激在致癌过程中的重要性体现在化学和环境肿瘤促进剂诱导活性氧产生的能力中。毫不奇怪，已经检查了许多抗氧化剂的潜在化学预防活性。虽然有强有力的临床前和流行病学证据支持抗氧化剂具有抗肿瘤特性的观点，但最近的人体研究显示了不同的结果。如果成功，本次拨款申请中提出的研究将为细胞对氧化应激的反应提供重要见解，特别是在肿瘤促进方面。重要的是，这些见解可能会带来更好的肿瘤发展化学预防方法。我们小组和其他人的研究表明，氧化应激会导致氧化甘油磷酸胆碱 (ox-GPC) 的产生，氧化甘油磷酸胆碱 (ox-GPC) 充当血小板激活因子受体 (PAF-R) 和过氧化物酶体增殖物激活受体 γ (PPAR?) 系统的激动剂。此外，我们和其他人提供的证据表明 PAF-R 和 PPAR？起到抑制肿瘤启动子诱导的过度增殖反应以及长期皮肤肿瘤的作用。我们假设 ox-GPC 具有 PAF-R 和 PPAR？激动剂活性已发展为针对肿瘤启动子诱导的肿瘤发展的细胞防御。它们通过抑制肿瘤启动子诱导的增生反应和随后的肿瘤发展来实现这一点。我们进一步提出，抗氧化剂通过阻止 ox-GPC 的产生来抑制这种保护反应。因此，我们期望添加回这些 ox-GPC 或 PAF-R 和/或 PPAR 的特定激动剂？将增强抗氧化疗法的化学预防活性。设计了三个具体目标来检验这些假设。 1.) 我们将首先验证两种不同的化学肿瘤启动子诱导小鼠表皮中这些ox-GPC的产生。然后我们将在小鼠表皮中验证局部应用 ox-GPC 以及定义的 PAF-R 和 PPAR？激动剂能够激活 PAF-R 和 PPAR?。这些反应的特异性将在缺乏 PAF-R (PAF-R(-/-)) 或表皮 PPAR 的基因敲除小鼠中得到验证？ （PPAR？（-/-））。 2.)接下来我们将演示PAF-R和PPAR？使用这些基因敲除小鼠模型抑制肿瘤启动子诱导的生长。然后我们将验证是否添加回外源 ox-GPC、PAF-R 激动剂或 PPAR？激动剂都可以增强抗氧化剂阻止肿瘤启动子诱导的过度增殖反应的能力。 3.)最后，使用正常小鼠以及这些基因敲除小鼠，我们将直接确定是否可以通过添加外源ox-GPC或特定PAF-R和/或PPAR来增强抗氧化剂的化学预防活性？激动剂。这些研究是我长期目标的一部分，旨在定义脂质激素参与肿瘤发展的基于受体的机制。公共健康相关性：所有肿瘤促进剂的两个共同特征是产生活性氧和诱导表皮持续过度增殖反应。我们小组最近的研究表明，活性氧诱导氧化甘油磷酸胆碱 (ox-GPC) 的产生，氧化甘油磷酸胆碱 (ox-GPC) 可以作为生长抑制性血小板激活因子受体 (PAF-R) 和过氧化物酶体增殖物激活受体 γ (PPAR?) 系统的激动剂。拟议的研究将确定肿瘤促进剂是否诱导 ox-GPC，通过激活生长抑制性 PAF-R 和/或 PPAR？在肿瘤发展中发挥保护功能。