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

15-PGDH 的小分子诱导：结肠癌化学预防的靶点

• 批准号: 9248208
• 负责人: John James Letterio
• 金额: $ 32.89万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248208
• 关键词: Address; Adenomatous Polyposis Coli; Alleles; Anabolism; Azoxymethane; Cancer Etiology; Cancer Model; Carcinogen exposure; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Clinical; Colitis; Colon; Colon Carcinoma; Colonic Neoplasms; Colonic Polyps; Coupling; Cyclooxygenase Inhibitors; Data; Dose; Enzyme Induction; Enzymes; Epidermal Growth Factor; Epithelial; FVB/N Mouse; Genes; Histone Deacetylase; Homeostasis; Human; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Intestinal Neoplasms; Laboratories; Lead; Lesion; Malignant Neoplasms; Metabolism; Modeling; Mucous Membrane; Mus; Oxidoreductase; PTGS2 gene; Pathway interactions; Patients; Play; Polyps; Pre-Clinical Model; Predisposition; Property; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Recording of previous events; Repression; Resistance; Role; Signal Pathway; Signal Transduction; Snails; Sodium Dextran Sulfate; Symptoms; TNF gene; Testing; Transcription Repressor/Corepressor; Transforming Growth Factor alpha; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Tumor Suppressor Genes; United States; adenoma; cancer chemoprevention; cancer therapy; carcinogenesis; celecoxib; colon carcinogenesis; cytokine; dietary supplements; efficacy testing; enzyme activity; high risk; inhibitor/antagonist; mouse model; novel; prevent; public health relevance; response; small molecule; tumor; tumorigenesis

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.

描述（由申请人提供）：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）作为结肠考克斯-2途径的内源性抑制剂和结肠肿瘤抑制基因发挥作用。现在有越来越多的证据支持这一假设，即15-PGDH的表达在粘膜上皮的稳态中起着重要作用，并且炎症介质对15-PDGH表达的抑制可能是结肠炎相关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表达的丧失是对考克斯-2抑制剂的应答的重要决定因素。因此，具有诱导15-PGDH表达能力的药剂可用作癌症化学预防的有效形式，并且可增强对考克斯-2抑制剂（例如塞来昔布或Celebrex）的应答或克服对该抑制剂的抗性。15-PGDH在正常结肠粘膜中高度表达，但这种酶的表达在人结肠癌中总是丢失。在小鼠中，编码15-PGDH的基因的破坏导致对结肠癌的易感性增加，增强了正常耐药的C57 BL/6 J菌株对氧化偶氮甲烷（AOM）诱导的结肠肿瘤的易感性，并导致APC+/Min中产生的结肠肿瘤增加。（多发性肠肿瘤）小鼠模型。3导致15-PGDH表达丧失的机制尚不完全清楚，但是已经通过涉及转录阻遏物Snail的机制证明了人结肠癌中组蛋白脱乙酰酶（HDAC）表达增加在15-PDGH表达阻遏中的作用。5此外，还证实了表皮生长因子信号传导和炎性细胞因子（TNF-α）对15-PGDH的抑制。这些数据支持炎症可能促进肿瘤发生的假设，部分是通过协调前列腺素生物合成和代谢酶的活性。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相关。三萜类化合物是一类调节多种信号传导途径的多功能小分子，并已在特定的癌症临床前模型中显示出化学预防活性。我们的初步数据证明了三萜类化合物的能力：a）以TGF-B依赖性方式诱导15-PGDH，B）在结肠炎相关结肠癌模型中恢复15-PGDH的表达，和c）在该模型中预防IBD的临床症状。上述观察结果是我们假设三萜类化合物的结肠癌化学预防需要TGF-β依赖性诱导15- PGDH的基础。

项目成果

The proinflammatory LTB4/BLT1 signal axis confers resistance to TGF-β1-induced growth inhibition by targeting Smad3 linker region.

• DOI: 10.18632/oncotarget.6146
• 发表时间: 2015-12-08
• 期刊: Oncotarget
• 作者: Jeon WK;Choi J;Park SJ;Jo EJ;Lee YK;Lim S;Kim JH;Letterio JJ;Liu F;Kim SJ;Kim BC
• 通讯作者: Kim BC