Lactate-mediated Fascin protrusions promote cell adhesion and migration in cervical cancer

Background: Lactate is associated with the poor prognosis of many human malignancies. Cervical cancer, one of main causes of women mortality worldwide, is aggressive and absent of effective pharmacological treatment, and its underlying mechanisms of progression remain elusive. Methods: The regulation of beta-catenin to fascin protrusion formation upon acidic lactate (Lactic acid [LA]) stimulation was evaluated through in beta-catenin or fascin deficiency cell line models by immunofluorescence assays, and subcellular fractionation. The effect of beta-catenin and fascin relocation by LA and its antagonist were evaluated by immunohistochemistry assay in patient tissues and mouse tumor xenograft model. Trypsin digestion, Transwell assay, cell proliferation in vitro was performed to explore the role of LA in the cell growth, adhesion and migration. Results: Low concentration of LA significantly promotes cytoskeleton remodeling via 'protrusion formation to increase cell adhesion and migration. Mechanistically, upon LA stimulation, beta-catenin diffuses from the cytoplasmic membrane into the nucleus, which in turn induces fascin nuclear-cytoplasm redistribution to the protrusion compartment. Moreover, the antagonist of LA sufficiently blocks the LA-mediated beta-catenin nuclear import, fascin nuclear export, and the growth and invasion of cervical cancer cells in vitro and in vivo using a murine xenograft model. Conclusions: This study uncovers beta-catenin-fascin axis as a key signal in response to extracellular lactate and indicates that antagonist of LA may serve as a potential clinical intervention for cancer development.

Automated summary

Lactate is associated with poor prognosis in many malignancies. This study reveals that lactate promotes cytoskeleton remodeling in cervical cancer cells, leading to increased cell adhesion and migration. The study also suggests that lactate antagonist could be a potential clinical intervention for cancer development.