Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis.
Broad Anti-tumor Activity of a Small Molecule that Selectively Targets the Warburg Effect and Lipogenesis.
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DOI：
10.1016/j.ccell.2015.05.007
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发表时间：
2015-07-13
期刊：
影响因子：
50.3
通讯作者：
Burris TP
中科院分区：
文献类型：
--
作者：
Flaveny CA;Griffett K;El-Gendy Bel-D;Kazantzis M;Sengupta M;Amelio AL;Chatterjee A;Walker J;Solt LA;Kamenecka TM;Burris TP
恶性细胞表现出有氧糖酵解（Warburg效应），并依赖于新生脂肪生成，从而维持快速增殖和抵抗细胞应激。核受体肝x受体（LXR）直接调控关键糖酵解和脂肪生成基因的表达。为了破坏这些致癌代谢途径，我们设计了一种LXR逆激动剂SR9243，可诱导LXR-辅抑制因子相互作用。在癌细胞中，SR9243通过降低糖酵解和脂肪生成基因的表达，显著抑制Warburg效应和脂肪生成。SR9243诱导肿瘤细胞凋亡，但不引起体重减轻、肝毒性或炎症。我们的研究结果表明LXR逆激动剂可能是一种有效的癌症治疗方法。
Malignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. In cancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach.