Deficiency of phospholipase A2 group 7 decreases intestinal polyposis and colon tumorigenesis in Apc(Min/+) mice.
Deficiency of phospholipase A2 group 7 decreases intestinal polyposis and colon tumorigenesis in Apc(Min/+) mice.
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DOI：
10.1158/0008-5472.can-12-2374
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发表时间：
2013-05-01
期刊：
影响因子：
11.2
通讯作者：
Stafforini DM
中科院分区：
文献类型：
--
作者：
Xu C;Reichert EC;Nakano T;Lohse M;Gardner AA;Revelo MP;Topham MK;Stafforini DM
血小板活化因子（PAF）是一种天然存在的磷脂，介导多种效应，如生理和病理炎症，免疫抑制和癌症。一些证据支持PAF在肿瘤发生中的积极和消极作用。PAF刺激细胞生长、致癌转化和转移，但也可限制增殖和诱导凋亡。生物学背景和微环境似乎可以确定PAF是否具有促癌或抗癌作用。为了研究PAF信号在结肠癌中的作用，我们使用缺乏磷脂酶A2组7（PLA 2G 7）表达的基因工程小鼠进行了基于细胞的体内研究，PLA 2G 7是一种特异性代谢PAF和结构相关甘油磷脂的酶。在Apc Min/+小鼠中，Pla 2g 7的缺乏有力地减少了肠息肉病和结肠肿瘤形成，表明PAF在以肿瘤抑制剂腺瘤性息肉病（Apc）的异常功能为特征的环境中具有抗肿瘤发生作用。在结肠上皮细胞中，暴露于PAF类似物导致Akt在丝氨酸-473处去磷酸化并诱导凋亡。这种反应的机制涉及β-arrestin 1和Akt磷酸酶PHLPP 2之间形成复合物，并激活细胞凋亡的内在途径。我们的研究结果表明，基于抑制PLA 2G 7活性或增加PAF介导的信号传导的策略，有望用于治疗APC突变的肠道恶性肿瘤。
Platelet-activating factor (PAF) is a naturally occurring phospholipid that mediates diverse effects such as physiological and pathological inflammation, immunosuppression, and cancer. Several lines of evidence support both positive and negative roles for PAF in carcinogenesis. PAF stimulates cell growth, oncogenic transformation and metastasis, but can also limit proliferation and induce apoptosis. The biological context and microenvironment appear to define whether PAF has pro- or anti-carcinogenic effects. To investigate the role of exacerbated PAF signaling in colon cancer, we conducted cell-based and in vivo studies using genetically engineered mice lacking expression of phospholipase A2 group 7 (PLA2G7), an enzyme that specifically metabolizes PAF and structurally related glycerophospholipids. Absence of Pla2g7 robustly decreased intestinal polyposis and colon tumor formation in Apc Min/+ mice, suggesting an anti-tumorigenic role for PAF in settings characterized by aberrant function of the tumor suppressor Adenomatous polyposis coli (Apc). In colonic epithelial cells, exposure to a PAF analog led to de-phosphorylation of Akt at serine-473 and induction of apoptosis. The mechanism of this response involved formation of a complex between β-arrestin 1 and the Akt phosphatase PHLPP2, and activation of the intrinsic pathway of apoptosis. Our results suggest that strategies based on inhibiting PLA2G7 activity or increasing PAF-mediated signaling, hold promise for the treatment of intestinal malignancies that harbor mutations in APC.