Hyperglycemic state and fluid shear stress affect metastatic breast cancer cell migration via focal adhesion kinase

Abstract

We tested how the diabetes-related hyperglycemic condition affects the migration of highly metastatic triple-negative breast cancer (TNBC) cells, MDA-MB-231, under a physiological fluid shear environment. MDA-MB-231 cells displayed a significantly enhanced migratory behavior under a high glucose condition (25 mM) specifically when exposed to flow at 15 dyne/cm2 shear stress. In contrast, the effect of fluid shear was marginal under low glucose (5 mM). Normal epithelial MCF-10A cells, on the other hand, showed increased migration by fluid shear under both low and high glucose conditions. The fluid shear-triggered MDA-MB-231 cell migration under high glucose was significantly abrogated by a focal adhesion kinase (FAK) inhibitor, supporting the mediatory role of FAK in MDA-MB-231 TNBC cell sensing of the high glucose-fluid shear environment during migration. The role of FAK was further demonstrated by the effects of FAK inhibitor on MDA-MB-231 cell migration in scratch wound healing and Boyden chamber migration assays. Our studies provide evidence that high glucose and fluid shear could jointly trigger MDA-MB-231 TNBC cell migration that requires FAK activity. These may provide improved mechanistic insights into how concurrent diabetes may impact the pro-metastatic behavior of breast cancer and suggest the impact of exploring FAK as a relevant therapeutic target.