An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway.
An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway.
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DOI：
10.1158/2159-8290.cd-11-0102
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发表时间：
2011-10
期刊：
影响因子：
28.2
通讯作者：
Mischel PS
中科院分区：
文献类型：
--
作者：
Guo D;Reinitz F;Youssef M;Hong C;Nathanson D;Akhavan D;Kuga D;Amzajerdi AN;Soto H;Zhu S;Babic I;Tanaka K;Dang J;Iwanami A;Gini B;Dejesus J;Lisiero DD;Huang TT;Prins RM;Wen PY;Robins HI;Prados MD;Deangelis LM;Mellinghoff IK;Mehta MP;James CD;Chakravarti A;Cloughesy TF;Tontonoz P;Mischel PS
胶质母细胞瘤（GBM）是成人最常见的恶性原发性脑肿瘤，也是所有癌症中最致命的一种。EGFR突变（EGFRvIII）和PI 3 K过度活化在GBM中很常见，促进肿瘤生长和存活，包括通过SREBP-1依赖性脂肪生成。胆固醇代谢在GBM发病机制中的作用、其与EGFR/PI 3 K信号传导的关联及其潜在的治疗靶向性尚不清楚。在这里，对GBM细胞系、异种移植模型和GBM临床样本（包括来自接受EGFR酪氨酸激酶抑制剂拉帕替尼治疗的患者）的研究揭示了通过LDL受体的EGFRvIII激活的PI 3 K/SREBP-1依赖性肿瘤存活途径。用肝X受体（LXR）激动剂GW 3965靶向LDLR可导致IDOL（LDLR的诱导性降解剂）介导的LDLR降解，并增加ABCA 1胆固醇外排转运蛋白的表达，从而在体内GBM模型中有效促进肿瘤细胞死亡。这些结果表明，EGFRvIII可通过LDLR的PI 3 K-SREBP-1依赖性上调来促进肿瘤存活，并表明LXR激动剂在GBM患者治疗中的作用。
Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. EGFR mutations (EGFRvIII) and PI3K hyperactivation are common in GBM, promoting tumor growth and survival, including through SREBP-1-dependent-lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. Here, studies in GBM cell lines, xenograft models and GBM clinical samples, including from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1-dependent tumor survival pathway through the LDL receptor. Targeting LDLR with the Liver X Receptor (LXR) agonist GW3965 caused IDOL (Inducible Degrader Of LDLR)-mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results demonstrate that EGFRvIII can promote tumor survival through PI3K-SREBP-1 dependent up-regulation of LDLR, and suggest a role for LXR agonists in the treatment of GBM patients.