Elevated hydrostatic pressure enhances the motility and enlarges the size of the lung cancer cells through aquaporin upregulation mediated by caveolin-1 and ERK1/2 signaling

Kao, Y.-C.Y.-C.KaoJheng, J.-R.J.-R.JhengPan, H.-J.H.-J.PanWEI-YU LIAOLee, C.-H.C.-H.LeePO-LING KUO2022-09-142022-09-1420170950-9232https://scholars.lib.ntu.edu.tw/handle/123456789/620022The mechanical characteristics presented in cancer microenvironment are known to have pivotal roles in cancer metastasis, which accounts for the leading cause of death from malignant tumors. However, while a uniformly distributed high interstitial fluid pressure (IFP) is a common feature in solid tumors, the effects of high IFP on the motility and invasiveness of cancer cells remain obscure. Using cell-culture devices that simulated increased IFP conditions by applying hydrostatic pressure (HP) ranging from 0 to 20 mm Hg to the cells, we found that the elevated HPs increased the migration speeds, invasiveness, cell volume, filopodial number and aquaporin-1 (AQP1), Snail and vinculin expression levels, as well as phosphorylation of caveolin-1 and extracellular signal-regulated kinase1/2 (ERK1/2), in the lung cancer cells CL1-5 and A549. The increases of migration speed and cell volume correlated temporally with the increase of AQP1 expression. The elevated HP-induced migration acceleration was hindered by AQP1 knockdown using small interfering RNA (siRNA) transfection. Inhibition of ERK1/2 phosphorylation using the mitogen-activated protein kinase kinase inhibitor PD98059 abrogated the elevated HP-induced AQP1 upregulation and migration acceleration in the cancer cells. Caveolin-1 knockdown by siRNA transfection attenuated the HP-induced, ERK1/2-depedent AQP1 upregulation and migration acceleration. Further biochemical studies revealed that the caveolin-1 activation-driven ERK1/2 signaling is mediated by Akt1/2 phosphorylation. By contrast, the elevated HPs had negligible effects on the migration speed and volume of normal bronchial epithelial cells. These results disclose a novel mechanism relating high IFP to the invasiveness of cancer cells and highlight potential targets to impede cancer spreading.enINTERSTITIAL FLUID PRESSURE; PROGNOSTIC-FACTORS; CERVIX CANCER; METASTASIS; TUMOR; MIGRATION; ACTIVATION; MELANOMA; INVASION; PATHWAYS[SDGs]SDG3[SDGs]SDG14Elevated hydrostatic pressure enhances the motility and enlarges the size of the lung cancer cells through aquaporin upregulation mediated by caveolin-1 and ERK1/2 signalingjournal article10.1038/onc.2016.255274990952-s2.0-84981164525WOS:000394168200013https://scholars.lib.ntu.edu.tw/handle/123456789/500817