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

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.