5-LOX-1 and Clinical Chemoprevention of Colon Tumors

描述（由申请方提供）：NSAID是结肠直肠癌有前途的化学预防剂，但其化学预防有效性是部分的。确定NSAIDs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剂非常重要。非甾体类抗炎药诱导细胞凋亡是其抗肿瘤作用的关键。我们在以前的研究中发现，（a）羟基十八碳二烯酸一种亚油酸产品（13-SHODE）及其生产酶15-脂氧合酶-1（15-LOX-1）在人结肠直肠癌中下调; 13-S-HODE恢复结肠直肠癌细胞的凋亡，（B）NSAID下调加塔-6表达以转录恢复触发人结肠直肠癌细胞凋亡的15-LOX-1表达，和（c）15-LOX-1下调过氧化物酶体增殖物激活受体（PPAR-delta）以触发细胞凋亡。为了测试NSAID的这些化学预防机制是否与临床相关，我们的提议将检验以下假设：NSAID下调加塔-6表达以恢复15-LOX-1表达，其增加13-S-HODE产生以下调PPAR-delta表达，从而诱导人结直肠肿瘤中的细胞凋亡。该假设将在塞来昔布治疗家族性腺瘤性息肉病综合征（FAP）患者的临床研究中进行如下检验：具体目的1：确定塞来昔布是否下调加塔-6表达以上调15-LOX-1表达，15-LOX-1表达进而下调PPAR-d表达以诱导人结肠直肠细胞凋亡。为了检测家族性腺瘤性息肉病综合征（FAP）患者结肠直肠息肉中的加塔-6、15-LOX-1和PPAR-delta表达、13-S-HODE水平和细胞凋亡率，我们将在用塞来昔布治疗6个月之前和之后测量结肠直肠息肉中的GATA-6、15-LOX-1和PPAR-delta表达、13-S-HODE水平和细胞凋亡率。具体目标二：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肠直肠息肉中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6个月前后的息肉数量来衡量对塞来昔布的反应，塞来昔布治疗前后13-S-HODE水平的变化。如果我们的假设得到证实，可以努力开发专门针对加塔-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.