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

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Abstract

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.

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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. All graphs corresponding to the datasets used in this study are included in this published article.

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Acknowledgements

Thanks to all the members who contributed to this study, including Jing He, Fang Wu, Xuedong Shu, Yao Wang, Junwei Zhang, Yue Yin, Jing Guo, Nihui Zhang, Tao Gao, Jun Shu, Guangpeng Zhang, Tingting Xu and others.

Funding

This works was supported by the National Natural Science Foundation of China (No. 31971257 and 32271397), and Natural Science Foundation of Sichuan Province (No. 2022NSFSC0360).

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  1. National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, PR China

    Huan Deng, Xuedong Shu, Yao Wang, Junwei Zhang, Yue Yin, Fang Wu & Jing He

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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by H.D. The main manuscript text was written by H.D. and all authors commented on previous versions of the manuscript. All authors reviewed the manuscript.

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Correspondence to Jing He.

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Deng, H., Shu, X., Wang, Y. et al. Matrix Stiffness Regulated Endoplasmic Reticulum Stress-mediated Apoptosis of Osteosarcoma Cell through Ras Signal Cascades. Cell Biochem Biophys 81, 839–850 (2023). https://doi.org/10.1007/s12013-023-01184-7

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