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

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

Research output: Contribution to journalArticle

60 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)14993-15007
Number of pages15
JournalOncotarget
Volume6
Issue number17
DOIs
StatePublished - 2015

Keywords

  • MiRNA-451
  • Multiple myeloma
  • PI3K/Akt/mTOR
  • Side population
  • Stemness

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma'. Together they form a unique fingerprint.

Cite this