Iron regulates MT1-MMP-mediated proMMP-2 activation and cancer cell invasion.

Cellular iron plays a crucial role in many crucial physiological processes. Excessive iron retention due to iron influx and efflux imbalance contributes to cancer development and proliferation, as well as malignant conversion. Membrane-type 1 matrix metalloproteinase (MT1-MMP) plays a crucial role in tumor invasion and metastasis, because this enzyme can degrade various extracellular matrix components and cleave membrane tethered proteins on the cell surface. Herein, we demonstrate that cellular iron regulates MT1-MMP-mediated proMMP-2 activation and thereby cancer cell invasion. Iron depletion downregulated MT1-MMP expression in cancer cells, accompanied by inhibition of proMMP-2 activation. Conversely, iron loading stimulated MT1-MMP expression and MT1-MMP-containing extracellular vesicle secretion, thereby promoting proMMP-2 activation, which was inhibited through antioxidant treatment. Iron chelator deferasirox suppressed cancer cell invasion but not fibroblasts. Thus, this study indicated that iron accumulation in cancer may contribute to not only cell proliferation but also invasion by activating the MT1-MMP-MMP-2 axis.