MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma.

Abstract

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.

• Authors: Juan Du, Shuyan Liu, Jie He, Xi Liu, Ying Qu, Wenqing Yan, Jianling Fan, Rong Li, Hao Xi, Weijun Fu, Chunyang Zhang, Jing Yang, Jian Hou
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 17 Pg. 14993-5007 (Jun 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25915427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene
• Antineoplastic Agents
• Arsenicals
• Benzopyrans
• MIRN451 microRNA, human
• MicroRNAs
• Oxides
• Bortezomib
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Melphalan
• Arsenic Trioxide

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Benzopyrans (pharmacology)
• Blotting, Western
• Bortezomib (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Melphalan (pharmacology)
• Mice, Inbred NOD
• Mice, SCID
• MicroRNAs (genetics)
• Multiple Myeloma (drug therapy, genetics, metabolism)
• Neoplastic Stem Cells (drug effects, metabolism)
• Oxides (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Side-Population Cells (drug effects, metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Transplantation, Heterologous
• Tuberous Sclerosis (genetics, metabolism)