Blockage of the mevalonate pathway overcomes the apoptotic resistance to MEK inhibitors with suppressing the activation of Akt in cancer cells.
Blockage of the mevalonate pathway overcomes the apoptotic resistance to MEK inhibitors with suppressing the activation of Akt in cancer cells.
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DOI：
10.18632/oncotarget.24696
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发表时间：
2018-04-13
期刊：
影响因子：
--
通讯作者：
Sakai T
中科院分区：
文献类型：
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作者：
Iizuka-Ohashi M;Watanabe M;Sukeno M;Morita M;Hoang NTH;Kuchimaru T;Kizaka-Kondoh S;Sowa Y;Sakaguchi K;Taguchi T;Sakai T
随着临床对MEK抑制剂在癌症治疗中的需求日益增加，克服对MEK抑制剂的耐药性是一个迫切需要解决的问题。许多报道表明，MEK抑制导致PI3K-Akt信号的激活，这可能导致细胞对MEK抑制剂产生凋亡抗性。我们在此证明，当与CH5126766或曲美替尼共处理时，使用抗脂药他汀类药物阻断甲羟戊酸途径可抑制MEK抑制后的Akt激活，并诱导显著的细胞凋亡。添加甲羟戊酸盐或焦磷酸香叶基可明显消除这些事件，表明香叶基基化蛋白与细胞对MEK抑制剂的凋亡抗性有关。此外，在机制上，CH5126766联合他汀类药物上调tnf相关的凋亡诱导配体（TRAIL），该配体依赖于甲羟戊酸途径的抑制，参与人乳腺癌MDA-MB-231细胞的凋亡诱导。本研究不仅揭示了甲羟戊酸途径可靶向增强MEK抑制剂的疗效，而且还提出MEK抑制剂与他汀类药物联合治疗可能是一种很有前景的治疗策略，可使癌细胞对凋亡敏感。
With increasing clinical demands for MEK inhibitors in cancer treatment, overcoming the resistance to MEK inhibitors is an urgent problem to be solved. Numerous reports have shown that MEK inhibition results in the activation of PI3K-Akt signaling, which may confer apoptotic resistance to MEK inhibitors. We here demonstrate that the blockade of the mevalonate pathway using the antilipidemic drug statins represses Akt activation following MEK inhibition and induces significant apoptosis when co-treated with CH5126766 or trametinib. These events were clearly negated by the addition of mevalonate or geranylgeranyl pyrophosphate, indicating that the protein geranylgeranylation is implicated in the apoptotic resistance to MEK inhibitors. Furthermore, mechanistically, the combined treatment of CH5126766 with statins upregulated TNF-related apoptosis-inducing ligand (TRAIL), which was dependent on inhibition of the mevalonate pathway and is involved in apoptosis induction in human breast cancer MDA-MB-231 cells. The present study not only revealed that the mevalonate pathway could be targetable to enhance the efficacy of MEK inhibitors, but also proposes that combinatorial treatment of MEK inhibitors with statins may be a promising therapeutic strategy to sensitize cancer cells to apoptosis.