Abrogation of LBH589-induced autolysosome maturation by Mevastatin promotes cell death in triple-negative breast cancer cells

2^nd Global Summit on Oncology & Cancer

March 12-14, 2018 Singapore

Xiaoxiao Jiang, Zhaohu Lin, Xinhui Kou and Yonghua Yang

Fudan University School of Pharmacy, China

Scientific Tracks Abstracts: J Cancer Sci Ther

Abstract :

There is a growing interest in the synergy of histone deacetylase inhibitors (HDACi) with other promising agents to achieve attractive therapeutic effects. We found that Mevastatin, a HMGCR reductase inhibitor, augments the antitumor efficacy of the HDACi LBH589 in triple-negative breast cancer (TNBC). The combination treatment with Mevastatin and LBH589 enhanced cell death of TNBC cells relying on a caspase-8 dependent apoptosis. Accompanied with the increased cell death, Mevastatin abrogated the autophagic flux triggered by LBH589, through activating LKB1-AMPK signaling and subsequently suppressing of mTOR, resulting in the blockade of VPS34/Beclin-1 complex formation and the inhibition of Rab7 prenylation, an active form of the small GTPase needed for autophagosome-lysosome fusion. In addition, our results indicate that disruption of autophagosome-lysosome fusion likely underlies Mevastatin-LBH589 synergistic anti-tumor effects. Furthermore, combinatorial treatment of metastatic TNBC with Mevastatin/LBH589 provoked a strong synergistic inhibition of tumor growth in MDA-MB-231 xenograft mice. These findings provide a potential therapeutic strategy for further clinical study and suggest that screening for novel autophagy modulators could be an efficient approach to strengthen the efficacy of HDACi in solid tumors.

Biography :

Xiaoxiao Jiang is a PhD student in the Department of Biochemistry & Pharmacology. She has received her Bachelor’s degree in Pharmacy from Shandong University and a Master’s degree in Tumor Pharmacology from Fudan University. Currently, her research project is on post-translational modification and development of anticancer drug screening assay. Her research interests include cancer immunotherapy and high-throughput genome sequencing.
Email:15111030035@fudan.edu.cn