title: Substrate Stiffness Influences Doxorubicin-Induced p53 Activation via ROCK2 Expression.
abstract: 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.
authors.affiliation: Frontiers of Innovative Research in Science and Technology, Konan University, 7-1-20 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ebata
authors.affiliation: Frontiers of Innovative Research in Science and Technology, Konan University, 7-1-20 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Mitsui
authors.affiliation: Frontiers of Innovative Research in Science and Technology, Konan University, 7-1-20 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Sugimoto
authors.affiliation: Frontiers of Innovative Research in Science and Technology, Konan University, 7-1-20 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Department of Bioscience, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan.
authors.forename: Keigo
authors.identifier: 0000-0002-4771-0494
authors.initials: K
authors.lastname: Araki
authors.affiliation: Laboratory for Comprehensive Bioimaging, Riken Qbic, 6-2-3 Furuedai, Suita, Osaka 565-0874, Japan; WPI, Immunology Frontier Research Center, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Machiyama
authors.affiliation: Laboratory for Mechanical Medicine, Nadogaya Research Institute, Nadogaya Hospital, 687-4 Kashiwa, Chiba 277-0032, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Harada
authors.affiliation: Department of Rehabilitation for the Movement Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities 4-1 Namiki, Tokorozawa, Saitama 359-8555, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Sawada
authors.affiliation: Laboratory for Comprehensive Bioimaging, Riken Qbic, 6-2-3 Furuedai, Suita, Osaka 565-0874, Japan; WPI, Immunology Frontier Research Center, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Frontiers of Innovative Research in Science and Technology, Konan University, 7-1-20 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan; Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki, Kanagawa 211-8533, Japan.
authors.forename: Keiko
authors.identifier: 0000-0002-8276-7277
authors.initials: K
authors.lastname: Kawauchi
mesh_terms: D001696:Biomechanical Phenomena / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004548:Elasticity; D005109:Extracellular Matrix / Q000737:chemistry* / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases