Matrix stiffness modulates ILK-mediated YAP activation to control the drug resistance of breast cancer cells

Xiang Qin; Xiaoying Lv; Ping Li; Rui Yang; Qiong Xia; Yu Chen; Yueting Peng; Li Li; Shun Li; Tingting Li; Ying Jiang; Hong Yang; Chunhui Wu; Chuan Zheng; Jie Zhu; Fengming You; Heng Wang; Jiong Chen; Yiyao Liu

doi:10.1016/j.bbadis.2019.165625

Matrix stiffness modulates ILK-mediated YAP activation to control the drug resistance of breast cancer cells

Biochim Biophys Acta Mol Basis Dis. 2020 Mar 1;1866(3):165625. doi: 10.1016/j.bbadis.2019.165625. Epub 2019 Nov 28.

Authors

Xiang Qin¹, Xiaoying Lv², Ping Li², Rui Yang², Qiong Xia², Yu Chen², Yueting Peng², Li Li¹, Shun Li¹, Tingting Li¹, Ying Jiang¹, Hong Yang¹, Chunhui Wu¹, Chuan Zheng³, Jie Zhu³, Fengming You³, Heng Wang⁴, Jiong Chen⁴, Yiyao Liu⁵

Affiliations

¹ Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China; Center for Information in Biology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China.
² Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China.
³ Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan, PR China.
⁴ State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, Jiangsu, PR China.
⁵ Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China; Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan, PR China; Center for Information in Biology, University of Electronic Science and Technology of China, Chengdu 610054, Sichuan, PR China. Electronic address: [email protected].

PMID: 31785406
DOI: 10.1016/j.bbadis.2019.165625

Abstract

One of the hallmarks of cancer progression is strong drug resistance during clinical treatments. The tumor microenvironment is closely associated with multidrug resistance, the optimization of tumor microenvironments may have a strong therapeutic effect. In this study, we configured polyacrylamide hydrogels of varying stiffness [low (10 kPa), intermediate (38 kPa) and high (57 kPa)] to simulate tissue physical matrix stiffness across different stages of breast cancer. After treatment with doxorubicin, cell survival rates on intermediate stiffness substrate are significantly higher. We find that high expression of ILK and YAP reduces the survival rates of breast cancer patients. Drug resistance is closely associated with the inactivation of the hippo pathway protein Merlin/MST/LATS and the activation of YAP. These results not only highlight the understanding of drug resistance mechanisms but also serve as a new basis for developing breast cancer treatment delivery systems.

Keywords: Drug resistance; ILK; Matrix stiffness; Mechanotransduction; YAP.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism*
Breast Neoplasms / metabolism*
Cell Line, Tumor
Cell Proliferation / physiology
Drug Resistance, Multiple / physiology*
Female
Humans
Phosphorylation / physiology
Protein Serine-Threonine Kinases / metabolism*
Signal Transduction / physiology
Survival Rate
Transcription Factors / metabolism*
Tumor Microenvironment / physiology
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
integrin-linked kinase
Protein Serine-Threonine Kinases