Chemopreventive signaling pathways

描述(由申请人提供)： 过氧化物酶体增殖激活受体-γ1(PPAR？)在结肠上皮细胞中高水平表达。噻唑烷二酮(TZD)药物激活该受体可抑制散发性结肠癌临床前期模型中癌前异常隐窝病灶(ACF)的形成。具有大量ACF的人类有患结肠癌的风险，临床前数据表明PPAR？可能会减轻有结肠癌风险的人类的ACF负担。然而，最近将TZD与心血管风险联系起来的数据表明，任何TZD都不太可能用于人类结肠癌的化学预防。因此，迫切需要弄清楚如何利用PPAR的化学预防潜力？同时传递潜在的有害副作用。我们的解决方案是使用PPAR？作为一种工具来识别参与抑制早期结肠癌细胞转化生长的基因组途径。这些途径可以被开发为PPAR下游的化学预防靶点。作为概念验证，我们使用系统生物学方法将钙调神经磷酸酶鉴定为结节PPAR？控制NFATc转录因子家族活性的靶点。PPAR？诱导内源性钙调神经磷酸酶抑制物(DSCR1)，该抑制物抑制钙调神经磷酸酶，导致NFATc活性抑制，随后下调参与侵袭和增殖的关键NFATc靶基因(COX2)和增殖(c-MYC)。钙调神经磷酸酶是FDA批准的几种药物的产物，我们将用这些药物来检验这样的假设，即钙调神经磷酸酶是PPAR？调节的途径的一个节点效应器，该途径控制早期结肠癌细胞的侵袭和增殖(特定目标1)。我们将确定钙调神经磷酸酶的遗传和药物抑制是否能阻止偶氮甲烷处理的小鼠ACF的形成(特定目标2)。最后，我们将挖掘我们的基因组数据，以确定与转化相关的PPAR？调节的其他途径，这些途径是FDA批准的药物的靶标。这些途径将在培养中验证和评估对增殖和/或侵袭的抑制，以期在体内测试它们的化学预防效果，作为我们未来目标的一部分。

DESCRIPTION (provided by applicant): Peroxisome proliferation-activated receptor-gamma 1 (PPAR?) is expressed at very high levels in colonic epithelial cells. Activation of this receptor by thiazolidinedione (TZD) drugs inhibits formation of pre-neoplastic aberrant crypt foci (ACF) in pre-clinical models of sporadic colon cancer. Humans who have large numbers of ACF are at risk for colon cancer, and the pre- clinical data suggest that activation of PPAR? might reduce the burden of ACF in humans who are at risk for colon cancer. However, recent data linking TZDs to cardiovascular risk make it unlikely that any TZD will ever be used for colon cancer chemoprevention in humans. There is therefore a pressing need to figure out how to take advantage of the chemopreventive potential of PPAR? while by passing potential deleterious side effects. Our solution is to use PPAR? as a tool to identify genomic pathways that are involved in suppression of transformed growth of early stage colon cancer cells. These pathways can then be developed as chemopreventive targets downstream of PPAR?. As proof-of-concept, we have used a systems biology approach to identify calcineurin as a nodal PPAR? target that controls the activity of the NFATc family of transcription factors. PPAR? induces an endogenous calcineurin inhibitor (DSCR1), which inhibits calcineurin, leading to inhibition of NFATc activity and subsequent downregulation of key NFATc target genes involved in invasion (COX2) and proliferation (c-MYC). Calcineurin is the product of several FDA-approved drugs which we will use to test the hypothesis that calcineurin is a nodal effector of a PPAR?-regulated pathway that controls invasion and proliferation of early stage colon cancer cells (Specific Aim 1). We will determine if genetic and pharmacological inhibition of calcineurin blocks ACF formation in azoxymethane-treated mice (Specific Aim 2). Finally, we will mine our genomic data to identify other PPAR?-regulated pathways that are linked to transformation and are targets of FDA-approved drugs. These pathways will be validated and evaluated for inhibition of proliferation and/or invasion in culture, with the view of testing their chemopreventive efficacy in vivo as part of our future goals.