Mefloquine disrupts cancer stem cells by inhibiting lysosomal RAB5/7 mediated mitophagy

ABSTRACT: BACKGROUND & AIMS Cancer stem cells (CSCs) establish hierarchy in tumor tissue and a critical role for acquisition of resistance to therapy. Thus, the targeting of CSCs is important. We focused on lysosome which characteristically upregulated in colon CSCs for the aim of CSC targeting and search for new maintenance of CSCs by analyzing the function of CSC targeting drug. METHODS Correlation of lysosomal activity and CSC markers was assessed and single sphere formation and limiting dilution assay were performed, to evaluate CSCs property. Additionally, in vitro and vivo, we evaluated that anticancer drugs, antimalarial drugs, antitumor effect by combining them, and changes in cancer stem cell hierarchy. We performed microarray analyses to compare gene expression patterns from the tumors of treated patient derived xenograft mice. RESULTS LC3B+ or Lysotracker+ cells were characteristically existed in CD44V9+/ CD133+ CSC fraction as a small cell subpopulation. Single sphere formation assay and limiting dilution assay showed higher sphere formation activity and higher tumorigenic activity of LC3B+ or Lysotracker+ cells compared to LC3B－or Lysotracker－cells. Mefloquine treatment significantly decreased CD44v9+/ CD133+ cell number than representative antimalarial drugs, chloroquine and hydroxychloroquine. Mefloquine demonstrated the synergic effect on oxaliplatin and irinotecan. In Microarray analysis, we elucidated that mefloquine disrupted lysosome pathway by inhibiting Rab5 and Rab7. In patient-derived colon cancer tissue xenografted (PDX) mouse model, combined treatment of mefloquine with oxaliplatin or irinotecan drastically abrogated the tumorigenic activity of cancer cells. CONCLUSIONS Lysosomal activity in CSCs is a promising therapeutic target, and repositioning of mefloquine to colon cancer together with conventional chemotherapeutic agent will be a promising strategy for cure of colon cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116023 | GEO | 2018/06/20

REPOSITORIES: GEO