Silencing IL-13Rα2 promotes glioblastoma cell death via endogenous signaling.
Silencing IL-13Rα2 promotes glioblastoma cell death via endogenous signaling.
复制标题
DOI：
10.1158/1535-7163.mct-10-1064
复制
发表时间：
2011-07
影响因子：
5.7
通讯作者：
Cathcart MK
中科院分区：
文献类型：
--
作者：
Hsi LC;Kundu S;Palomo J;Xu B;Ficco R;Vogelbaum MA;Cathcart MK
多形性胶质母细胞瘤（GBM）是最致命的癌症形式之一，尽管有最佳的药物治疗，但在诊断后2年内的存活率仅为13-27%。我们推测，独特的IL-13 R α2诱饵受体的存在阻止GBM凋亡。该受体对IL-13（白细胞介素-13）具有高亲和力，结合细胞因子，并竞争性抑制由IL-13引发的细胞内信号级联。在缺乏IL-13 R α2诱饵受体的细胞中，IL-13启动15-脂氧合酶-1（15-LOX-1）的产生，这与细胞凋亡有关。我们的研究小组和其他人已经表明，15-LOX-1的诱导与结直肠癌、胰腺癌和前列腺癌中的肿瘤细胞死亡相关。15-LOX-1如何诱导细胞凋亡仍不清楚。GBM细胞中的初步证据暗示了过氧化物酶体增殖物激活受体γ（PPARγ）介导的凋亡过程。15-LOX-1代谢产物可以调节PPARγ，并且PPARγ的活化可以抑制肿瘤生长。我们假设在GBM中，IL-13可以诱导15-LOX-1，其通过经由PPARγ的信号传导调节细胞凋亡，并且IL-13 R α2的表达阻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点。用siRNA敲低IL-13 R α2显著诱导15-LOX-1表达，促进细胞凋亡并减少体内GBM肿瘤生长。这些发现确定了消除内源性IL-13信号传导的阻断和促进细胞凋亡的机制，并表征了15-LOX-1在GBM细胞凋亡中的作用。确定一个机制的途径，可以有针对性的药物干预将有应用的影响，开发新的和有效的治疗GBM。
Glioblastoma multiforme (GBM) is one of the most lethal forms of cancer, with a survival rate of only 13–27% 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 IL-13 (Interleukin-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 peroxisome proliferator-activated receptor gamma (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 siRNA 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 promotion of apoptosis and characterizes a role for 15-LOX-1 in GBM apoptosis. Identifying a mechanistic pathway that can be targeted for pharmacological intervention will have applied implications to developing novel and effective treatments for GBM.