Migration and invasion of
cancer cells constitute fundamental processes in
tumor progression and
metastasis. Migratory
cancer cells commonly upregulate expression of
plasminogen activator inhibitor 1 (PAI1), and PAI1 correlates with poor prognosis in
breast cancer. However, mechanisms by which PAI1 promotes migration of
cancer cells remain incompletely defined. Here we show that increased PAI1 drives rearrangement of the actin cytoskeleton, mitochondrial fragmentation, and glycolytic metabolism in
triple-negative breast cancer (TNBC) cells. In two-dimensional environments, both stable expression of PAI1 and treatment with recombinant PAI1 increased migration, which could be blocked with the specific inhibitor
tiplaxtinin. PAI1 also promoted invasion into the extracellular matrix from coculture spheroids with human mammary fibroblasts in
fibrin gels. Elevated cellular PAI1 enhanced cytoskeletal features associated with migration, actin-rich migratory structures, and reduced actin stress fibers. In orthotopic
tumor xenografts, we discovered that TNBC cells with elevated PAI1 show
collagen fibers aligned perpendicular to the
tumor margin, an established marker of invasive
breast tumors. Further studies revealed that PAI1 activates ERK signaling, a central regulator of motility, and promotes mitochondrial fragmentation. Consistent with known effects of mitochondrial fragmentation on metabolism, fluorescence lifetime imaging microscopy of endogenous
NADH showed that PAI1 promotes glycolysis in cell-based assays, orthotopic
tumor xenografts, and lung
metastases. Together, these data demonstrate for the first time that PAI1 regulates
cancer cell metabolism and suggest targeting metabolism to block motility and
tumor progression. IMPLICATIONS: We identified a novel mechanism through which
cancer cells alter their metabolism to promote
tumor progression.