5-LOX-1 and Clinical Chemoprevention of Colon Tumors

描述（由申请人提供）：NSAID 是结直肠癌有前途的化学预防剂，但其化学预防效果是部分的。定义非甾体抗炎药的化学预防机制对于确定可以开发更好的化学预防剂的分子靶标非常重要。 NSAID 诱导细胞凋亡对其抗肿瘤作用至关重要。我们在之前的研究中发现，（a）羟基十八碳二烯酸（13-SHODE），一种亚油酸产物，及其产生酶15-脂氧合酶-1（15-LOX-1）在人类结直肠癌中表达下调； 13-S-HODE 恢复结直肠癌细胞的凋亡；(b) NSAID 下调 GATA-6 表达，以转录方式恢复 15-LOX-1 表达，从而触发人结直肠癌细胞凋亡；(c) 15-LOX-1 下调过氧化物酶体增殖物激活受体 (PPAR)-δ (PPAR-delta) 触发细胞凋亡。测试 NSAID 的这些化学预防机制是否具有临床相关性；我们的提案将检验以下假设：NSAIDs 下调 GATA-6 表达以恢复 15-LOX-1 表达，从而增加 13-S-HODE 的产生以下调 PPAR-delta 表达，从而诱导人类结直肠肿瘤细胞凋亡。这一假设将在塞来昔布治疗家族性腺瘤性息肉病综合征 (FAP) 患者的临床研究中得到检验，具体如下： 具体目标 1：确定塞来昔布是否下调 GATA-6 表达，上调 15-LOX-1 表达，进而下调 PPAR-d 表达，诱导人结直肠细胞凋亡！我们将测量家族性腺瘤性息肉病综合征 (FAP) 患者接受塞来昔布治疗 6 个月前后结直肠息肉中 GATA-6、15-LOX-1 和 PPAR-δ 的表达、13-S-HODE 水平以及细胞凋亡率。具体目标 2：为了确定 FAP 患者对塞来昔布的化学预防反应与塞来昔布对人结直肠息肉中 15-LOX-1 的影响之间的关系，我们将根据 FAP 患者接受塞来昔布治疗前后 6 个月的息肉数量来测量对塞来昔布的反应，并将化学预防反应（由平均息肉数量的变化定义）与塞来昔布治疗前后的 13-S-HODE 水平。如果我们的假设得到证实，就可以致力于开发专门针对 GATA-6 和 15-LOX-1 信号通路的化学预防干预措施。

DESCRIPTION (provided by applicant): NSAIDs are promising chemopreventive agents in colorectal cancers, however their chemopreventive effectiveness is partial. Defining NSAIDs' chemopreventive mechanisms is important to identify molecular targets that can lead to develop better chemopreventive agents. NSAIDs induction of apoptosis is crucial to their antitumorigenic effects. We have found in previous studies that (a) hydroxyoctadecadienoic acid (13-SHODE), a linoleic acid product, and its producing enzyme, 15-lipoxygenase-1 (15-LOX-1), are downregulated in human colorectal cancers; and 13-S-HODE restores apoptosis in colorectal cancer cells, (b) NSAIDs downregulate GATA-6 expression to transcriptionally restore 15-LOX-1 expression that triggers apoptosis in human colorectal cancer cells, and (c) 15-LOX-1 downregulates the peroxisome proliferatoractivated receptor (PPAR)- delta (PPAR-delta) to trigger apoptosis. To test whether these chemopreventive mechanisms of NSAIDs are clinically relevant; our proposal will examine the following hypothesis: NSAIDs downregulate GATA-6 expression to restore 15-LOX-1 expression, which increases 13-S-HODE production to downregulate PPAR-delta expression, thereby inducing apoptosis in human colorectal tumors. This hypothesis will be tested in a clinical study of celecoxib treatment of patients with familial adenomatous polyposis syndrome (FAP) as follows: Specific Aim 1: To determine whether celecoxib downregulates GATA-6 expression to upregulate 15-LOX-1 expression, which in turn downregulates PPAR-d expression to induce apoptosis in human colorecta! polyps, we will measure GATA-6, 15-LOX-1 and PPAR-delta expression, 13-S-HODE levels, and apoptosis rates in colorectal polyps before and after 6 months of treatment with celecoxib in patients with familial adenomatous polyposis syndrome (FAP). Specific Aim 2: To define the relationship between chemopreventive response to celecoxib in patients with FAP' and the effects of celecoxib on 15-LOX-1 in human colorectal polyps, we will measure the response to celecoxib in terms of polyp number before and after 6 months of treatment with celecoxib in patients with FAP and will correlate the chemopreventive response (defined by the changes in mean polyp number) to 13-S-HODE levels before and after celecoxib treatment. If our hypothesis is confirmed, efforts can be directed to develop chemopreventive interventions that specifically target the GATA-6 and 15-LOX-1 signaling pathway.