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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Mahiro Iizuka-Ohashi1,2, Motoki Watanabe1, Mamiko Sukeno1, Mie Morita1, Ngoc Thi Hong Hoang3, Takahiro Kuchimaru3, Shinae Kizaka-Kondoh3, Yoshihiro Sowa1, Koichi Sakaguchi2, Tetsuya Taguchi2 and Toshiyuki Sakai1
1Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
2Division of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
3Department of Life Science and Technology, School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
Motoki Watanabe, email: [email protected]
Keywords: MEK inhibitor resistance; mevalonate pathway; statin; Akt; apoptosis
Received: August 09, 2017 Accepted: February 24, 2018 Published: April 13, 2018
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.
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