Leukotriene Biosynthesis: Inflammation and Cancer

含有非活性P53肿瘤抑制基因的细胞的基因组完整性的丧失在肿瘤学中具有严重的后果。野生型p53wt的失活可能源于它的体细胞突变或它在胞浆中的分离，在胞浆中它不能作为转录因子发挥作用。P53wt在以炎症性乳腺癌和神经母细胞瘤为代表的侵袭性肿瘤或以腺瘤性息肉为代表的癌前病变中的胞浆分离不涉及其体细胞突变或病毒癌蛋白的隔离。因此，p53wt的表观遗传失活必须涉及其他未知的参与者和过程。我们将检验三个综合假说：1)与急性或慢性炎症相关的癌症风险的增加，部分源于p53wt的化学损伤，它扰乱了它的构象，并有利于它在胞浆中的分离，胞浆是一个与其肿瘤抑制功能不相容的细胞室。2)用亲电性二十烷基类化合物或其他亲电性炎症介质使p53wt失活，将降低传统抗肿瘤药物的疗效，并恶化预后。肿瘤发生可能以不同的速率或通过不同的分子途径进行，这取决于p53wt失活的性质(体细胞突变与表观遗传失活)。3)以脂氧合酶和环氧合酶催化生物合成途径产生的某些二十烷基类为代表的亲电性炎症脂质介质，通过以下方式促成这种表观遗传形式的p53失活：i)与p53wt直接反应或ii)与控制p53构象和功能完整性的蛋白质间接反应。我们的初步数据来自我们的观察，即独立于p53wt作用的代理可能在实验上与灭活p53wt的代理没有区别，除非人们故意检查这两种不同的可能性。暴露在含有亲电取代基的脂类中的细胞在胞浆中积累了一种构象错乱的p53wt形式，将其排除在细胞核之外，使其无法反式激活p53wt反应基因，从而降低了对p53wt依赖的细胞凋亡的易感性。P53wt失活的一种新的表观遗传学机制的发现和表征对癌症的诊断、治疗和预后具有直接意义。我们的相关发现使细胞能够通过p53wt不依赖的途径传播细胞凋亡，这对癌症的药理学具有直接意义。我们预计，我们的研究将确定一种与癌症风险增加相关的新的分子过程，以及二十烷类化合物在调节基因组稳定性方面的新作用。

Loss of genomic integrity in cells harboring an inactive p53 tumor suppressor has grave consequences in oncology. Inactivation of wild type p53wt can originate from its somatic mutation or from its segregation in the cytosol, where it is inoperative as a transcription factor. Cytoplasmic segregation of p53wt in aggressive neoplasms, typified by inflammatory breast cancer and neuroblastoma, or in pre-neoplastic lesions, typified by adenomatous polyps does not involve its somatic mutation or its sequestration by viral oncoproteins. Thus, epigenetic inactivation of p53wt must involve other, unknown participants and processes. We will test three integrated hypotheses: 1) Elevated risks of cancers associated with acute or chronic inflammation originate, in part, from a chemical impairment of p53wt that deranges its conformation and favors its segregation in the cytosol, a cellular compartment that is incompatible with its tumor suppressor function. 2) Inactivation of p53wt by electrophilic eicosanoids, or other electrophilic mediators of inflammation, will diminish the efficacy of conventional anti- neoplastic agents and worsen prognosis. Oncogenesis may proceed at different rates or via different molecular pathways depending on the nature of p53wt inactivation (somatic mutation versus epigenetic inactivation). 3) Electrophilic lipid mediators of inflammation, typified by certain eicosanoids derived from the lipoxygenase and cyclooxygenase catalytic pathways of biosynthesis, contribute to this epigenetic form of p53 inactivation via: i) direct reaction with p53wt or ii) indirect reaction with proteins that govern the conformational and functional integrity of p53. Our preliminary data emerge from our observations that agents acting independently of p53wt may be experimentally indistinguishable from agents inactivating p53wt unless one deliberately examines these two, separate possibilities. Cells exposed to lipids with an electrophilic substituent accumulate a conformationally deranged form p53wt in their cytosol, exclude it from their nucleus, disable its transactivation of p53wt responsive genes, and thereby reduce their susceptibility to p53wt -dependent apoptosis. Discovery and characterization of a novel, epigenetic mechanism for the inactivation of p53wt is directly significant for diagnosis, treatment, and prognosis of cancer. Our related discovery of a process that enables cells to propagate apoptosis via p53wt- independent pathways is directly significant to the pharmacology of cancer. We anticipate that our investigations will identify a novel molecular process associated with elevated risks of cancer and a novel role for eicosanoids in the modulation of genomic stability.