Leukotriene Biosynthesis: Inflammation and Cancer

在肿瘤抑制基因p53失活的细胞中，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细胞质中的分离，在细胞质中它作为转录因子不起作用。侵袭性肿瘤（以炎性乳腺癌和神经母细胞瘤为典型）或瘤前病变（以腺瘤性息肉为典型）中p53wt的细胞质分离不涉及其体细胞突变或被病毒癌蛋白隔离。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。我们将测试三个综合假设：1)与急性或慢性炎症相关的癌症风险升高，部分源于p53wt的化学损伤，这种损伤使其构象紊乱，有利于其在细胞质中分离，细胞质是一种与其肿瘤抑制功能不相容的细胞室。2)亲电性类二十烷酸或其他亲电性炎症介质使p53wt失活，会降低常规抗肿瘤药物的疗效，使预后恶化。根据p53wt失活的性质（体细胞突变与表观遗传失活），肿瘤发生可能以不同的速率或通过不同的分子途径进行。3)炎症的亲电性脂质介质，以生物合成的脂加氧酶和环加氧酶催化途径产生的某些类二十烷化合物为代表，通过以下途径促进p53的表观遗传失活：i)与p53wt的直接反应或ii)与控制p53构象和功能完整性的蛋白质的间接反应。我们的初步数据来自于我们的观察，即独立作用于p53wt的药物在实验上可能与灭活p53wt的药物难以区分，除非有人故意检查这两种单独的可能性。细胞暴露于具有亲电取代基的脂质中，在细胞质中积累构象紊乱的p53wt，将其从细胞核中排除，使其对p53wt应答基因的反激活失效，从而降低其对p53wt依赖性凋亡的易感性。p53wt失活的一种新的表观遗传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通过不依赖于p53wt的途径传播凋亡的过程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升高相关的新分子过程，以及类二十烷酸在调节基因组稳定性中的新作用。

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.