Small Molecule Induction of 15-PGDH: A Target in Colon Cancer Chemoprevention

描述(申请人提供)：环氧合酶途径被认为是癌症化学预防和治疗的重要靶点。前列腺素(PG)降解酶15-羟基前列腺素脱氢酶(15-PGDH)是结肠COX-2途径的内源性抑制因子，也是结肠肿瘤抑制基因。目前有越来越多的证据支持这一假设，即15-PGDH的表达在粘膜上皮细胞的动态平衡中起重要作用，炎性介质抑制15-PDGH的表达可能是结肠炎相关性结肠癌发生的重要步骤。特别是，最近的数据表明，在癌症化学预防的背景下，15-PGDH表达的丧失是对COX-2抑制剂反应的一个重要决定因素。因此，具有诱导15-PGDH表达能力的药物可能成为一种有效的癌症化学预防形式，并可能增强对COX-2抑制剂(如塞来昔布或Celebrex(R))的反应或克服其耐药性。15-PGDH在正常结肠粘膜中高表达，但在人类结肠癌中却总是表达缺失。在小鼠中，编码15-PGDH的基因的破坏导致结肠癌的易感性增加，增强了正常耐药的C57BL/6J株对偶氮甲烷(AOM)诱导的结肠癌的敏感性，并导致在APC/Min(多发性肠道肿瘤)小鼠模型中发生的结肠癌增加。3导致这种15-PGDH表达缺失的机制尚不完全清楚，但已经证明在人类结肠癌中组蛋白脱乙酰酶(HDAC)的表达增加在抑制15-PDGH表达中的作用是通过涉及转录抑制因子Snail5的机制。表皮生长因子信号转导和炎性细胞因子(TNF-a)对15-PGDH的抑制作用也已被证实。这些数据支持炎症可能促进肿瘤发生的假说，部分是通过对前列腺素生物合成和新陈代谢酶活性的协同影响。为了解决这个问题，我们的实验室现在探索三萜类化合物(天然和合成)诱导15-PGDH表达的能力，以及这种酶的诱导是否与结肠癌的有效化学预防有关。三萜类化合物是一类多功能小分子，调节多种信号通路，并在特定的临床前癌症模型中显示出化学预防活性。我们的初步数据表明，三萜类化合物能够：a)以转化生长因子-b依赖的方式诱导15-PGDH，b)在结肠炎相关性结肠癌模型中恢复15-PGDH的表达，以及c)在该模型中预防IBD的临床症状。上面概述的观察结果是我们假设的基础，即三萜类化合物化学预防结肠癌需要依赖于转化生长因子-b诱导的15-前列腺素脱氢酶。

DESCRIPTION (provided by applicant): The cyclooxygenase pathway is considered an important target in the chemoprevention and therapy of cancer. The prostaglandin (PG) degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), functions as an endogenous inhibitor of the colonic COX-2 pathway and as a colon tumor suppressor gene. There is now accumulating evidence that support the hypothesis that expression of 15-PGDH plays an important role in mucosal epithelial homeostasis, and that repression of 15-PDGH expression by inflammatory mediators may be an important step in colitis associated colon carcinogenesis. In particular, recent data indicate that the loss of 15-PGDH expression is an important determinant of the response to inhibitors of COX-2 in the context of cancer chemoprevention. Therefore, agents with a capacity to induce the expression of 15-PGDH may serve as an effective form of cancer chemoprevention, and may either enhance the response to or overcome the resistance to COX-2 inhibitors (such as celecoxib or Celebrex(R)). 15-PGDH is highly expressed in normal colon mucosa, but the expression of this enzyme is invariably lost in human colon cancers. In mice, a disruption of the gene encoding 15-PGDH leads to an increase in susceptibility to colon cancer, enhancing the susceptibility of the normally resistant C57BL/6J strain to colon tumor induction with azoxymethane (AOM) and leading to an increase in colon tumors arising in the APC+/Min (multiple intestinal neoplasia) mouse model.3 Mechanisms leading to this loss of 15-PGDH expression are not entirely clear, but a role for increased expression of histone deacetylase (HDAC) in human colon cancers in the repression of 15-PDGH expression has been demonstrated through a mechanism that involves the transcriptional repressor, Snail.5 In addition, repression of 15-PGDH by epidermal growth factor signaling and by inflammatory cytokines (TNF-a) has also been demonstrated. These data support the hypothesis that inflammation may promote tumorigenesis, in part, through coordinated effects on activities of enzymes of both prostaglandin biosynthesis and metabolism. To address this question, our laboratory now explores the ability of triterpenoids (natural and synthetic) to induce the expression of 15-PGDH, and whether an induction of this enzyme is associated with effective chemoprevention of colon cancer. The triterpenoids are a class of multifunctional small molecules that regulate multiple signaling pathways and have demonstrated chemopreventive activity in specific preclinical models of cancer. Our preliminary data demonstrate the ability of triterpenoids to: a) induce 15-PGDH in a TGF-b-dependent manner, b) restore expression of 15-PGDH in a model of colitis associated colon cancer and c) prevent clinical symptoms of IBD in this model. The observations outlined above are the basis for our hypothesis that colon cancer chemoprevention by triterpenoids requires a TGF-b-dependent induction of 15- PGDH.