American Association for Cancer Research
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15357163mct190358-sup-220095_3_supp_5908969_q16xnq.pdf (223.77 kB)

Supplementary Figure S3 from Eribulin Suppresses Clear Cell Sarcoma Growth by Inhibiting Cell Proliferation and Inducing Melanocytic Differentiation Both Directly and Via Vascular Remodeling

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posted on 2023-04-03, 16:08 authored by 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, Norifumi Naka

Supplementary Figure S3 shows western blot in Hewga-CCS and MP-CCS-SY cells treated with CoCl2 in the absence or presence of SCH772984, and qRT-PCR in both CCS cells treated with CoCl2.

Funding

Japan Society for the Promotion of Science

Osaka Medical Research Foundation for Intractable Diseases

Japan Orthopaedics and Traumatology Foundation

Japan Agency for Medical Research and Development

History

ARTICLE 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.