Mevastatin blockade of autolysosome maturation stimulates LBH589-induced cell death in triple-negative breast cancer cells

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// Zhaohu Lin 1, 3 , Zhuqing Zhang 1 , Xiaoxiao Jiang 1 , Xinhui Kou 1 , Yong Bao 1 , Huijuan Liu 1 , Fanghui Sun 1 , Shuang Ling 2 , Ning Qin 3 , Lan Jiang 4 , Yonghua Yang 1 1 Department of Pharmacology and Biochemistry, School of Pharmacy Fudan University, Shanghai 201203, China 2 Interdisciplinary Research Institute, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China 3 Chemical Biology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai 201203, China 4 Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA Correspondence to: Yonghua Yang, email: yonghuayang@hotmail.com Keywords: breast cancer, mevastatin, HDAC inhibitor, LBH589, autophagy Received: November 30, 2016 Accepted: January 11, 2017 Published: January 27, 2017 ABSTRACT 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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