Trabectedin is a promising antitumor agent potentially inducing melanocytic differentiation for clear cell sarcoma

Takafumi Ueda,Hironari Tamiya,Keiko Kaneko,Kazuyuki Itoh,Sho Nakai,Akira Myoui,Takaaki Nakai,Hideki Yoshikawa,Shutaro Yamada,Naohiro Yasuda,Satoshi Takenaka,Kenichiro Hamada,Nobuhito Araki,Norifumi Naka,Yoshinori Imura,Hidetatsu Outani

doi:10.1002/cam4.1130

Takafumi Ueda, Hironari Tamiya + Show 14 more

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https://doi.org/10.1002/cam4.1130

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Abstract

Clear cell sarcoma is an aggressive soft tissue sarcoma and highly resistant to conventional chemotherapy and radiation therapy. This devastating disease is defined by EWSR1‐ATF1 fusion gene resulting from chromosomal translocation t(12;22)(q13;q12) and characterized by melanocytic differentiation. A marine‐derived antineoplastic agent, trabectedin, inhibits the growth of myxoid liposarcoma and Ewing sarcoma by causing adipogenic differentiation and neural differentiation, respectively. In this study, we examined the antitumor effects and mechanism of action of trabectedin on human clear cell sarcoma cell lines. We showed that trabectedin decreased the cell proliferation of five clear cell sarcoma cell lines in a dose‐dependent manner in vitro and reduced tumor growth of two mouse xenograft models. Flow cytometry and immunoblot analyses in vitro and immunohistochemical analysis in vivo revealed that trabectedin‐induced G2/M cell cycle arrest and apoptosis. Furthermore, trabectedin increased the expression of melanocytic differentiation markers along with downregulation of ERK activity in vitro and the rate of melanin‐positive cells in vivo. These results suggest that trabectedin has potent antitumor activity against clear cell sarcoma cells by inducing cell cycle arrest, apoptosis, and, in part, by promoting melanocytic differentiation through inactivation of ERK signaling. Our present study indicates that trabectedin is a promising differentiation‐inducing agent for clear cell sarcoma.

Highlights

Clear cell sarcoma (CCS) is a rare but highly malignant soft tissue sarcoma that typically develops in the tendons and aponeuroses of children and young adults [1, 2]
Flow cytometry analyses showed that 1 nmol/L trabectedin induced G2/M cell-cycle arrest, and 10 nmol/L trabectedin increased the number of cells in sub-G1 phase in Hewga- CCS and KAS cells (Fig. 2A)
The expression of the EWSR1-activating transcription factor 1 (ATF1) fusion protein was not affected by the treatment of trabectedin in both cells (Fig 4B). These results suggested that the upregulation of m icrophthalmia-associated transcription factor (MITF) protein levels by trabectedin treatment was neither attributable to the transcriptional activation of MITF nor mediated by the interaction between trabectedin and EWSR1-ATF1

Summary

Introduction

Clear cell sarcoma (CCS) is a rare but highly malignant soft tissue sarcoma that typically develops in the tendons and aponeuroses of children and young adults [1, 2]. CCS is very resistant to conventional chemotherapy and radiation therapy. There is an urgent need for novel therapeutic approaches against CCS. Cytogenetic analysis of CCS revealed the presence of translocation t(12;22)(q13;q12), resulting in a chimeric EWSR1-ATF1 gene [11,12,13,14]. CCS was originally considered to be a melanoma of soft tissue origin and was called “malignant melanoma of soft parts.”. From this point of view, CCS has been proposed to arise from a progenitor CCS was originally considered to be a melanoma of soft tissue origin and was called “malignant melanoma of soft parts.” From this point of view, CCS has been proposed to arise from a progenitor

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