Mevastatin blockade of autolysosome maturation stimulates LBH589-induced cell death in triple-negative breast cancer cells.
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.
Department of Pharmacology and Biochemistry, School of Pharmacy Fudan University, Shanghai 201203, China.|Chemical Biology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai 201203, China.
Zhaohu
Z
Lin
Department of Pharmacology and Biochemistry, School of Pharmacy Fudan University, Shanghai 201203, China.
Zhuqing
Z
Zhang
Department of Pharmacology and Biochemistry, School of Pharmacy Fudan University, Shanghai 201203, China.
Xiaoxiao
X
Jiang
Department of Pharmacology and Biochemistry, School of Pharmacy Fudan University, Shanghai 201203, China.
Xinhui
X
Kou
Department of Pharmacology and Biochemistry, School of Pharmacy Fudan University, Shanghai 201203, China.
Yong
Y
Bao
Department of Pharmacology and Biochemistry, School of Pharmacy Fudan University, Shanghai 201203, China.
Huijuan
H
Liu
Department of Pharmacology and Biochemistry, School of Pharmacy Fudan University, Shanghai 201203, China.
Fanghui
F
Sun
Interdisciplinary Research Institute, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Shuang
S
Ling
Chemical Biology, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Shanghai 201203, China.
Ning
N
Qin
Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA.
Lan
L
Jiang
Department of Pharmacology and Biochemistry, School of Pharmacy Fudan University, Shanghai 201203, China.
Yonghua
Y
Yang
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1 / Q000378:metabolism; D045744:Cell Line, Tumor; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000077767:Panobinostat; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays; D020691:rab GTP-Binding Proteins / Q000096:biosynthesis; D000090802:rab7 GTP-Binding Proteins
D000970:Antineoplastic Agents; C491997:BECN1 protein, human; D000071186:Beclin-1; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; C012258:mevastatin; D000077767:Panobinostat; D008148:Lovastatin; C546842:MTOR protein, human; D058546:Class III Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D020691:rab GTP-Binding Proteins
HDAC inhibitor; LBH589; autophagy; breast cancer; mevastatin