Quinacrine inhibits cMET-mediated metastasis and angiogenesis in breast cancer stem cells

Abstract: A trans-membrane receptor, mesenchymal-epithelial transition factor (cMET), is responsible for cancer metastasis and angiogenesis. A very little is known about the role of cMET in cancer stem cells (CSCs). Quinacrine (QC), a bioactive agent, has shown anti-CSCs activity. Here, the role of QC in deregulation of cMET-mediated metastasis and angiogenesis has been systematically evaluated in vitro in highly-metastatic-breast-CSCs (mBCSCs), ex vivo in patient-derived-breast-cancer-stem-cells (PDBCSCs) and in vivo in xenograft mice model systems. Cell proliferation, migration, invasion and representative metastasis markers were upregulated in cMET-overexpressed cells and QC exposure inhibited these processes in both mBCSCs and PDBCSCs. Interestingly, metastasis was inhibited after silencing of cMET and very less significant alteration of the process was noted in QC-treated cMET-silenced cells. Increased in vascularization, and cell-cell tube formation, and enhanced MMP2 and MMP9 enzymatic activities were noted after cMET-overexpression but these processes got reversed after cMET knockdown. In addition, QC inhibited angiogenesis after cMET-overexpression, but failed to change in cMET-silenced cells. Reduction of tumor volume and decreased expression of metastatic and angiogenic markers were also noted in xenograft mice after QC treatment. Furthermore, QC inhibited cMET activity by de-phosphorylation of its tyrosine residues (Y1234 and Y1356) and downregulation of its downstream cascade.