5-LOX-1 and Clinical Chemoprevention of Colon Tumors

描述(申请人提供)：非类固醇抗炎药是结直肠癌有希望的化学预防药物，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以开发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。我们在以往的研究中发现：(A)亚油酸产物羟基十八碳二烯酸(13-SHODE)及其产生酶15-脂氧合酶-1(15-LOX-1)在人类结直肠癌中表达下调；13-S-HODE可恢复结直肠癌细胞的凋亡；(B)非类固醇抗炎药下调GATA-6的表达，从转录上恢复15-LOX-1的表达，从而触发结直肠癌细胞的凋亡；以及(C)15-LOX-1下调过氧化物酶体增殖物激活受体(PPAR)-Delta(PPAR-Delta)的表达，从而触发细胞凋亡。为了验证NSAIDs的这些化学预防机制是否与临床相关；我们的建议将检验以下假设：NSAIDs下调GATA-6的表达，恢复15-LOX-1的表达，从而增加13-S-HODE的产量，下调PPAR-Delta的表达，从而诱导人结直肠癌细胞的凋亡。这一假设将在塞来昔布治疗家族性腺瘤性息肉综合征(FAP)患者的临床研究中得到验证，具体目的如下：1：确定塞来昔布是否下调GATA-6的表达，上调15-LOX-1的表达，进而下调PPAR-d的表达，从而诱导人结肠直肠细胞的凋亡！我们将检测家族性腺瘤性息肉综合征患者应用塞来昔布治疗6个月前后大肠息肉组织中GATA-6、15-LOX-1和PPAR-Delta的表达、13-S-HODE水平和细胞凋亡率。具体目的2：为了明确FAP患者对塞来昔布的化学预防反应与塞来昔布对人类大肠息肉中15-LOX-1的影响之间的关系，我们将通过对FAP患者使用塞来昔布治疗6个月前后息肉数量的变化来衡量对塞来昔布的反应，并将塞来昔布治疗前后的化学预防反应与13-S-HODE水平相关联。如果我们的假设得到证实，就可以努力开发专门针对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.