ROCK inhibition induces terminal adipocyte differentiation and suppresses tumorigenesis in chemoresistant osteosarcoma cells

Nobuhiro Takahashi, Hiroyuki Nobusue, Takatsune Shimizu, Eiji Sugihara, Sayaka Yamaguchi-Iwai, Nobuyuki Onishi, Haruko Kunitomi, Tatsuo Kuroda, Hideyuki Saya

Research output: Contribution to journalArticle

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Abstract

Tumors comprise heterogeneous cell types including cancer stem cells (CSC), progenitor cells, and differentiated cells. Chemoresistance is a potential cause of relapse and a key characteristic of CSC, but the development of novel therapeutic approaches for targeting these cells has been limited. We previously established osteosarcoma-initiating (OSi) cells by introducing the gene for c-Myc into bone marrow stromal cells of Ink4a/Arf knockout mice. These OSi cells are composed of two distinct clones: highly tumorigenic cells (AX cells), similar to bipotent committed osteochondral progenitor cells, and tripotent cells of low tumorigenicity (AO cells), similar to mesenchymal stemcells. Here we show that depolymerization of the actin cytoskeleton induces terminal adipocyte differentiation and suppresses tumorigenesis in chemoresistant OSi cells. In contrast to AX cells, AO cells were highly resistant to conventional chemotherapeutic agents such as doxorubicin and were thus identified as chemoresistant cells. Inhibition of Rho-associated coiled-coil containing protein kinase (ROCK) elicited terminal adipocyte differentiation in chemoresistant AO cells through negative regulation of the transcriptional coactivator megakaryoblastic leukemia 1 associated with actin depolymerization. The clinically administered ROCK inhibitor fasudil significantly suppressed growth in vitro and tumorigenicity in vivo of chemoresistant AO cells as well as of OSi cells. Our findings thus suggest a new therapeutic strategy based on the induction of trans-terminal differentiation via modulation of actin cytoskeleton dynamics for therapyresistant osteosarcoma stem cells.

Original languageEnglish
Pages (from-to)3088-3099
Number of pages12
JournalCancer Research
Volume79
Issue number12
DOIs
Publication statusPublished - 2019 Jun 15

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Osteosarcoma
Adipocytes
Carcinogenesis
Stem Cells
Neoplastic Stem Cells
Actin Cytoskeleton
rho-Associated Kinases
myc Genes
Mesenchymal Stromal Cells
Knockout Mice
Doxorubicin
Actins
Leukemia

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

ROCK inhibition induces terminal adipocyte differentiation and suppresses tumorigenesis in chemoresistant osteosarcoma cells. / Takahashi, Nobuhiro; Nobusue, Hiroyuki; Shimizu, Takatsune; Sugihara, Eiji; Yamaguchi-Iwai, Sayaka; Onishi, Nobuyuki; Kunitomi, Haruko; Kuroda, Tatsuo; Saya, Hideyuki.

In: Cancer Research, Vol. 79, No. 12, 15.06.2019, p. 3088-3099.

Research output: Contribution to journalArticle

Takahashi, N, Nobusue, H, Shimizu, T, Sugihara, E, Yamaguchi-Iwai, S, Onishi, N, Kunitomi, H, Kuroda, T & Saya, H 2019, 'ROCK inhibition induces terminal adipocyte differentiation and suppresses tumorigenesis in chemoresistant osteosarcoma cells', Cancer Research, vol. 79, no. 12, pp. 3088-3099. https://doi.org/10.1158/0008-5472.CAN-18-2693
Takahashi, Nobuhiro ; Nobusue, Hiroyuki ; Shimizu, Takatsune ; Sugihara, Eiji ; Yamaguchi-Iwai, Sayaka ; Onishi, Nobuyuki ; Kunitomi, Haruko ; Kuroda, Tatsuo ; Saya, Hideyuki. / ROCK inhibition induces terminal adipocyte differentiation and suppresses tumorigenesis in chemoresistant osteosarcoma cells. In: Cancer Research. 2019 ; Vol. 79, No. 12. pp. 3088-3099.
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