MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma
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Juan Du1,*, Shuyan Liu1,*, Jie He1, Xi Liu1, Ying Qu1, Wenqing Yan1, Jianling Fan1, Rong Li1, Hao Xi1, Weijun Fu1, Chunyang Zhang1, Jing Yang2 and Jian Hou1
1 Department of Hematology, The Myeloma and Lymphoma Center, Changzheng Hospital, The Second Military Medical University, Shanghai, China
2 Department of Lymphoma/Myeloma, Division of Cancer Medicine and Center for Cancer Immunology Research, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
* These authors have contributed equally to this work
Jian Hou, email:
Keywords: multiple myeloma; side population; miRNA-451; PI3K/Akt/mTOR; stemness
Received: January 09, 2015 Accepted: March 18, 2015 Published: April 12, 2015
Side population (SP) cells are an enriched source of cancer-initiating cells with stemness characteristics, generated by increased ABC transporter activity, which has served as a unique hallmark for multiple myeloma (MM) stem cell studies. Here we isolated and identified MM SP cells via Hoechst 33342 staining. Furthermore, we demonstrate that SP cells possess abnormal cell cycle, clonogenicity, and high drug efflux characteristics, all of which are features commonly seen in stem cells. Interestingly, we found that bortezomib, As2O3, and melphalan all affected apoptosis and clonogenicity in SP cells. We followed by characterizing the miRNA signature of MM SP cells and validated the specific miR-451 target tuberous sclerosis 1 (TSC1) gene to reveal that it activates the PI3K/Akt/mTOR signaling in MM SP cells. Inhibition of miR-451 enhanced anti-myeloma novel agents’ effectiveness, through increasing cells apoptosis, decreasing clonogenicity, and reducing MDR1 mRNA expression. Moreover, the novel specific PI3K/Akt/mTOR signaling inhibitor S14161 displayed its prowess as a potential therapeutic agent by targeting MM SP cells. Our findings offer insights into the mechanisms regulating MM SP cells and provide a novel strategy to overcome resistance to existing therapies against myeloma.
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