Matrix Stiffness Regulated Endoplasmic Reticulum Stress-mediated Apoptosis of Osteosarcoma Cell through Ras Signal Cascades.

The modulating effects of matrix stiffness on spreading and apoptosis of tumor cells have been well recognized. Nevertheless, the detail road map leading to the apoptosis and the underlying mechanisms governing the cell apoptosis have remained to be elucidated. To this aim, we provided a tunable elastic hydrogel matrix that promoted cell adhesion by modifying the surface of polyacrylamide with polydopamine, with stiffness value of 1, 10, 30, and 250 kPa, respectively. While the cell spreading increased and the apoptosis decreased with the matrix stiffness, such modulating effect of matrix on cell spreading exhibited different time evolvement behaviors as a function of stiffness, which likely led to surprisingly similar apoptosis rates for the 30 kPa and 250 kPa samples. Matrix stiffness mediated the spreading and apoptosis of MG-63 cells by regulating cell adhesion to matrix and in particular cytoskeletal organization, which was dependent on Ras, Rap1 and PI3K-Akt signaling pathways and finally led to the apoptosis of cancer cells dominated by endoplasmic reticulum stress pathway. Our results provided an insight into the regulation of tumor cell fate by the mechanical clues of ECM, which would have implication for future cancer research and the design of novel anticancer materials.