Mevastatin blockade of autolysosome maturation stimulates LBH589-induced cell death in triple-negative breast cancer cells
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Zhaohu Lin1,3, Zhuqing Zhang1, Xiaoxiao Jiang1, Xinhui Kou1, Yong Bao1, Huijuan Liu1, Fanghui Sun1, Shuang Ling2, Ning Qin3, Lan Jiang4, Yonghua Yang1
1Department of Pharmacology and Biochemistry, School of Pharmacy Fudan University, Shanghai 201203, China
2Interdisciplinary Research Institute, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
3Chemical Biology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai 201203, China
4Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA
Yonghua Yang, email: email@example.com
Keywords: breast cancer, mevastatin, HDAC inhibitor, LBH589, autophagy
Received: November 30, 2016 Accepted: January 11, 2017 Published: January 27, 2017
Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, and combining a HDACi with other agents is an attractive therapeutic strategy in solid tumors. We report here that mevastatin increases HDACi LBH589-induced cell death in triple-negative breast cancer (TNBC) cells. Combination treatment inhibited autophagic flux by preventing Vps34/Beclin 1 complex formation and downregulating prenylated Rab7, an active form of the small GTPase necessary for autophagosome-lysosome fusion. This means that co-treatment with mevastatin and LBH589 activated LKB1/AMPK signaling and subsequently inhibited mTOR. Co-treatment also led to cell cycle arrest in G2/M phase and induced corresponding expression changes of proteins regulating the cell cycle. Co-treatment also increased apoptosis both in vitro and in vivo, and reduced tumor volumes in xenografted mice. Our results indicate that disruption of autophagosome-lysosome fusion likely underlies mevastatin-LBH589 synergistic anticancer effects. This study confirms the synergistic efficacy of, and demonstrates a potential therapeutic role for mevastatin plus LBH589 in targeting aggressive TNBC, and presents a novel therapeutic strategy for further clinical study. Further screening for novel autophagy modulators could be an efficient approach to enhance HDACi-induced cell death in solid tumors.
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