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BioMed Research International
Volume 2017 (2017), Article ID 5158961, 10 pages
Research Article

Substrate Stiffness Influences Doxorubicin-Induced p53 Activation via ROCK2 Expression

1Frontiers of Innovative Research in Science and Technology, Konan University, 7-1-20 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan
2Department of Bioscience, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan
3Laboratory for Comprehensive Bioimaging, Riken Qbic, 6-2-3 Furuedai, Suita, Osaka 565-0874, Japan
4WPI, Immunology Frontier Research Center, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan
5Laboratory for Mechanical Medicine, Nadogaya Research Institute, Nadogaya Hospital, 687-4 Kashiwa, Chiba 277-0032, Japan
6Department of Rehabilitation for the Movement Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities 4-1 Namiki, Tokorozawa, Saitama 359-8555, Japan
7Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, Aichi 466-8550, Japan
8Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki, Kanagawa 211-8533, Japan

Correspondence should be addressed to Keiko Kawauchi

Received 30 July 2016; Revised 3 December 2016; Accepted 12 December 2016; Published 16 January 2017

Academic Editor: Esmaiel Jabbari

Copyright © 2017 Takahiro Ebata et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The physical properties of the extracellular matrix (ECM), such as stiffness, are involved in the determination of the characteristics of cancer cells, including chemotherapy sensitivity. Resistance to chemotherapy is often linked to dysfunction of tumor suppressor p53; however, it remains elusive whether the ECM microenvironment interferes with p53 activation in cancer cells. Here, we show that, in MCF-7 breast cancer cells, extracellular stiffness influences p53 activation induced by the antitumor drug doxorubicin. Cell growth inhibition by doxorubicin was increased in response to ECM rigidity in a p53-dependent manner. The expression of Rho-associated coiled coil-containing protein kinase (ROCK) 2, which induces the activation of myosin II, was significantly higher when cells were cultured on stiffer ECM substrates. Knockdown of ROCK2 expression or pharmacological inhibition of ROCK decreased doxorubicin-induced p53 activation. Our results suggest that a soft ECM causes downregulation of ROCK2 expression, which drives resistance to chemotherapy by repressing p53 activation.