Theranostics 2016; 6(12):2209-2224. doi:10.7150/thno.15584
Lycorine Downregulates HMGB1 to Inhibit Autophagy and Enhances Bortezomib Activity in Multiple Myeloma
1. The State Key Laboratory of Medical Genetics & School of Life Sciences, Central South University, Changsha 410078, China.
2. Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300020, China.
3. Department of Medicine, University of California, Irvine, CA 92697, USA.
4. Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics
College of Biology
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China.
5. Cancer Research Institute, Central South University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education; Key Laboratory of Carcinogenesis, National Health and Family Planning Commission, Changsha 410078, China.
*These authors contributed equally to this work.
Multiple myeloma (MM) is largely incurable and drug-resistant. Novel therapeutic approaches such as inhibiting autophagy or rational drug combinations are aimed to overcome this issue. In this study, we found that lycorine exhibits a promising anti-proliferative activity against MM in vitro and in vivo by inhibiting autophagy. We identified High mobility group box 1 (HMGB1), an important regulator of autophagy, as the most aberrantly expressed protein after lycorine treatment and as a critical mediator of lycorine activity. Gene expression profiling (GEP) analysis showed that higher expression of HMGB1 is linked with the poor prognosis of MM. This correlation was further confirmed in human bone marrow CD138+ primary myeloma cells and MM cell lines. Mechanistically, proteasomal degradation of HMGB1 by lycorine inhibits the activation of MEK-ERK thereby decreases phosphorylation of Bcl-2 resulting in constitutive association of Bcl-2 with Beclin-1. In addition, we observed higher HMGB1 expression in bortezomib resistant cells and the combination of bortezomib plus lycorine was highly efficient in vitro and in vivo myeloma models as well as in re-sensitizing resistant cells to bortezomib. These observations indicate lycorine as an effective autophagy inhibitor and reveal that lycorine alone or in combination with bortezomib is a potential therapeutic strategy.
Keywords: Lycorine, Multiple myeloma, Autophagy, HMGB1, Bortezomib resistance.
Roy M, Liang L, Xiao X, Peng Y, Luo Y, Zhou W, Zhang J, Qiu L, Zhang S, Liu F, Ye M, Zhou W, Liu J. Lycorine Downregulates HMGB1 to Inhibit Autophagy and Enhances Bortezomib Activity in Multiple Myeloma. Theranostics 2016; 6(12):2209-2224. doi:10.7150/thno.15584. Available from http://www.thno.org/v06p2209.htm