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Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Eribulin Suppresses Clear Cell Sarcoma Growth by Inhibiting Cell Proliferation and Inducing Melanocytic Differentiation Both Directly and Via Vascular Remodeling

Sho Nakai, Hironari Tamiya, Yoshinori Imura, Takaaki Nakai, Naohiro Yasuda, Toru Wakamatsu, Takaaki Tanaka, Hidetatsu Outani, Satoshi Takenaka, Kenichiro Hamada, Akira Myoui, Nobuhito Araki, Takafumi Ueda, Hideki Yoshikawa and Norifumi Naka
Sho Nakai
1Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
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Hironari Tamiya
2Musculoskeletal Oncology Service, Osaka International Cancer Institute, Osaka, Japan.
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Yoshinori Imura
2Musculoskeletal Oncology Service, Osaka International Cancer Institute, Osaka, Japan.
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Takaaki Nakai
3Department of Orthopaedic Surgery, Kawachi General Hospital, Kawachi, Japan.
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Naohiro Yasuda
1Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
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Toru Wakamatsu
2Musculoskeletal Oncology Service, Osaka International Cancer Institute, Osaka, Japan.
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  • ORCID record for Toru Wakamatsu
Takaaki Tanaka
2Musculoskeletal Oncology Service, Osaka International Cancer Institute, Osaka, Japan.
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Hidetatsu Outani
1Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
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Satoshi Takenaka
1Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
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Kenichiro Hamada
1Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
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Akira Myoui
1Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
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  • ORCID record for Akira Myoui
Nobuhito Araki
4Department of Orthopaedic Surgery, Ashiya Municipal Hospital, Ashiya, Japan.
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Takafumi Ueda
5Department of Orthopaedic Surgery, Osaka National Hospital, Osaka, Japan.
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Hideki Yoshikawa
1Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
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Norifumi Naka
1Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
2Musculoskeletal Oncology Service, Osaka International Cancer Institute, Osaka, Japan.
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  • For correspondence: naka-no@mc.pref.osaka.jp
DOI: 10.1158/1535-7163.MCT-19-0358 Published March 2020
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Abstract

Clear cell sarcoma (CCS) is a rare but chemotherapy-resistant and often fatal high-grade soft-tissue sarcoma (STS) characterized by melanocytic differentiation under control of microphthalmia-associated transcription factor (MITF). Eribulin mesilate (eribulin) is a mechanistically unique microtubule inhibitor commonly used for STS treatment, particularly liposarcoma and leiomyosarcoma. In this study, we examined the antitumor efficacy of eribulin on four human CCS cell lines and two mouse xenograft models. Eribulin inhibited CCS cell proliferation by inducing cell-cycle arrest and apoptosis, shrunk CCS xenograft tumors, and increased tumor vessel density. Eribulin induced MITF protein upregulation and stimulated tumor cell melanocytic differentiation through ERK1/2 inactivation (a MITF negative regulator) in vitro and in vivo. Moreover, tumor reoxygenation, probably caused by eribulin-induced vascular remodeling, attenuated cell growth and inhibited ERK1/2 activity, thereby upregulating MITF expression and promoting melanocytic differentiation. Finally, downregulation of MITF protein levels modestly debilitated the antiproliferative effect of eribulin on CCS cells. Taken together, eribulin suppresses CCS through inhibition of cell proliferation and promotion of tumor differentiation by acting both directly on tumor cells and indirectly through tumor reoxygenation.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:742–54

  • Received April 2, 2019.
  • Revision received September 16, 2019.
  • Accepted November 27, 2019.
  • Published first December 3, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (3)
March 2020
Volume 19, Issue 3
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Eribulin Suppresses Clear Cell Sarcoma Growth by Inhibiting Cell Proliferation and Inducing Melanocytic Differentiation Both Directly and Via Vascular Remodeling
Sho Nakai, Hironari Tamiya, Yoshinori Imura, Takaaki Nakai, Naohiro Yasuda, Toru Wakamatsu, Takaaki Tanaka, Hidetatsu Outani, Satoshi Takenaka, Kenichiro Hamada, Akira Myoui, Nobuhito Araki, Takafumi Ueda, Hideki Yoshikawa and Norifumi Naka
Mol Cancer Ther March 1 2020 (19) (3) 742-754; DOI: 10.1158/1535-7163.MCT-19-0358

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Eribulin Suppresses Clear Cell Sarcoma Growth by Inhibiting Cell Proliferation and Inducing Melanocytic Differentiation Both Directly and Via Vascular Remodeling
Sho Nakai, Hironari Tamiya, Yoshinori Imura, Takaaki Nakai, Naohiro Yasuda, Toru Wakamatsu, Takaaki Tanaka, Hidetatsu Outani, Satoshi Takenaka, Kenichiro Hamada, Akira Myoui, Nobuhito Araki, Takafumi Ueda, Hideki Yoshikawa and Norifumi Naka
Mol Cancer Ther March 1 2020 (19) (3) 742-754; DOI: 10.1158/1535-7163.MCT-19-0358
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