Department of Cell Biology, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio 44195, USA.
Mol Cancer Ther. 2011 Jul;10(7):1149-60. doi: 10.1158/1535-7163.MCT-10-1064. Epub 2011 May 19.
Glioblastoma multiforme (GBM) is one of the most lethal forms of cancer, with a survival rate of only 13% to 27% within 2 years of diagnosis despite optimal medical treatment. We hypothesize that the presence of a unique IL-13Rα2 decoy receptor prevents GBM apoptosis. This receptor has a high affinity for interleukin-13 (IL-13), binds the cytokine, and competitively inhibits the intracellular signaling cascade initiated by IL-13. In cells lacking the IL-13Rα2 decoy receptor, IL-13 initiates the production of 15-lipoxygenase-1 (15-LOX-1), which has been implicated in cellular apoptosis. Our group and others have shown that induction of 15-LOX-1 correlates with tumor cell death in colorectal, pancreatic, and prostate cancer. How 15-LOX-1 induces apoptosis remains unclear. Preliminary evidence in GBM cells implicates an apoptotic process mediated by PPARγ. 15-LOX-1 metabolites can modulate PPARγ and activation of PPARγ can suppress tumor growth. We hypothesize that in GBM, IL-13 can induce 15-LOX-1, which regulates cell apoptosis via signaling through PPARγ and that expression of IL-13Rα2 prevents apoptosis and contributes to tumor growth. Our in vitro and in vivo data support this. Knocking down IL-13Rα2 with short interfering RNA dramatically induces 15-LOX-1 expression, promotes apoptosis, and reduces GBM tumor growth in vivo. These findings identify a mechanism for eliminating the blockade of endogenous IL-13 signaling and for promotion of apoptosis, and characterize a role for 15-LOX-1 in GBM apoptosis. Identifying a mechanistic pathway that can be targeted for pharmacologic intervention will have applied implications to developing novel and effective treatments of GBM.
胶质母细胞瘤（GBM）是最致命的癌症之一，尽管进行了最佳的医疗治疗，在诊断后 2 年内的存活率仅为 13%至 27%。我们假设存在独特的 IL-13Rα2 诱饵受体可防止 GBM 细胞凋亡。该受体对白细胞介素-13（IL-13）具有高亲和力，与细胞因子结合，并竞争性抑制由 IL-13 引发的细胞内信号级联反应。在缺乏 IL-13Rα2 诱饵受体的细胞中，IL-13 会引发 15-脂氧合酶-1（15-LOX-1）的产生，该酶与细胞凋亡有关。我们的研究小组和其他研究小组已经表明，15-LOX-1 的诱导与结直肠、胰腺和前列腺癌中的肿瘤细胞死亡相关。15-LOX-1 如何诱导细胞凋亡尚不清楚。在 GBM 细胞中的初步证据表明，凋亡过程是由 PPARγ 介导的。15-LOX-1 代谢产物可以调节 PPARγ，而 PPARγ 的激活可以抑制肿瘤生长。我们假设在 GBM 中，IL-13 可以诱导 15-LOX-1，通过 PPARγ 信号转导调节细胞凋亡，而 IL-13Rα2 的表达可防止细胞凋亡并促进肿瘤生长。我们的体外和体内数据支持这一假设。用短发夹 RNA 敲低 IL-13Rα2 可显著诱导 15-LOX-1 的表达，促进细胞凋亡，并减少体内 GBM 肿瘤的生长。这些发现确定了一种消除内源性 IL-13 信号传导阻断并促进细胞凋亡的机制，并阐明了 15-LOX-1 在 GBM 细胞凋亡中的作用。确定一种可以靶向进行药物干预的机制途径，将对开发新的和有效的 GBM 治疗方法具有实际意义。
