Fluid Shear Stress Induces Cell Cycle Arrest in Human Urinary Bladder Transitional Cell Carcinoma Through Bone Morphogenetic Protein Receptor-Smad1/5 Pathway.

Abstract

Mechanical force generated from the interstitial fluid flow inside and surrounding tissue has been known to play a significant role in cancer pathophysiology. In this study, we aimed to investigate the role of laminar shear stress (LSS) in modulating the cell cycle of human bladder transitional carcinoma (BFTC-905) cells which are frequently stimulated by not only the interstitial fluid flow, but also the urine flow transported from kidney to bladder in the urinary tract. The BFTC-905 cells were subjected to 0-12 dynes cm-2 LSS for 1, 4, 8, or 12h, respectively, followed by cellular and molecular assays for investigations of cell cycle regulation protein expressions, cell growth rates, and the potential mechanism. The results showed that the LSS with ≥ 8 dynes cm-2 for ≥ 8h significantly increased protein expressions of cyclin B1, Wee1, p21, and p-CDK1(Tyr15) (p < 0.05 for each), but conversely decreased protein expressions of cyclin A2, D1, E1, and CDK-1, -2, -4, and -6 (p < 0.05 for each) in the BFTC-905 cells, indicating that a G2/M cell cycle arrest was obtained after shearing stimulation. Furthermore, our data demonstrated that the LSS-induced G2/M arrest and the corresponding changes in cell cycle regulatory protein expressions were modulated by bone morphogenetic protein (BMP) receptor-Smad1/5 signaling pathway. Our findings provided evidences for the effect of mechanical microenvironment on urothelial cancer pathobiology and generated insights into mechanism of LSS-regulated bladder tumor cell cycle.