5-LOX-1 and Clinical Chemoprevention of Colon Tumors

描述（由申请人提供）：非甾体抗炎药是一种很有前景的结直肠癌化学预防药物，但其化学预防效果是部分的。明确非甾体抗炎药的化学预防机制对于确定分子靶点，从而开发出更好的化学预防药物非常重要。非甾体抗炎药诱导细胞凋亡是其抗肿瘤作用的关键。我们在之前的研究中发现(a)亚油酸产物羟基十八烯二烯酸（13-SHODE）及其产生酶15-脂氧合酶-1 （15-LOX-1）在人类结直肠癌中下调；(b)非甾体抗炎药下调GATA-6表达，转录恢复人结直肠癌细胞中触发细胞凋亡的15-LOX-1表达；(c) 15-LOX-1下调过氧化物酶体增殖激活受体(PPAR)- δ (PPAR- δ)触发细胞凋亡。检验非甾体抗炎药的这些化学预防机制是否具有临床相关性；我们的提议将检验以下假设：nsaid下调GATA-6的表达以恢复15-LOX-1的表达，从而增加13-S-HODE的产生以下调PPAR-delta的表达，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验证，具体目的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综合征（FAP）患者在塞来昔布治疗前后6个月结肠直肠息肉中GATA-6、15-LOX-1和PPAR-delta的表达、13-S-HODE水平和细胞凋亡率。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类结肠直肠息肉15-LOX-1的影响之间的关系，我们将在FAP患者使用塞来昔布治疗6个月前后测量塞来昔布对息肉数量的反应，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13-S-HODE水平相关联。如果我们的假设得到证实，我们就可以开发专门针对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.