AURKA/PLK1/CDC25C Axis as a Novel Therapeutic Target in INI1-Deficient Epithelioid Sarcoma

Inoue, Akitomo; Outani, Hidetatsu; Imura, Yoshinori et al.

Cancer Science, 2025

Number of Access:1,117（2025-07-24 02:18 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/100350

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Title
AURKA/PLK1/CDC25C Axis as a Novel Therapeutic Target in INI1-Deficient Epithelioid Sarcoma
Creator
CreatorName
Inoue, Akitomo
NRID
1000060727965 1000060727965
researchmap permalink
h-otani h-otani
Scopus Author ID
6506224785 6506224785
CreatorName
Outani, Hidetatsu
NRID
1000040772687 1000040772687
ORCID
0000-0002-0430-5894 0000-0002-0430-5894
researchmap permalink
yoshinori.imura yoshinori.imura
Scopus Author ID
55807487700 55807487700
CreatorName
Imura, Yoshinori
NRID
1000000930207 1000000930207
researchmap permalink
nakaisho nakaisho
Scopus Author ID
57194235635 57194235635
CreatorName
Nakai, Sho
CreatorName
Takami, Haruna
CreatorName
Kotani, Yuki
NRID
1000060978261 1000060978261
ORCID
0009-0000-4617-0409 0009-0000-4617-0409
CreatorName
Mae, Hirokazu
NRID
1000030448435 1000030448435
ORCID
0000-0002-5107-8209 0000-0002-5107-8209
researchmap permalink
okadaseiji okadaseiji
Scopus Author ID
35079139100 35079139100
CreatorName
Okada, Seiji
Subject
alisertib
aurora kinase A
epithelioid sarcoma
polo-like kinase 1
soft tissue sarcoma
Description
Inoue A., Outani H., Imura Y., et al. AURKA/PLK1/CDC25C Axis as a Novel Therapeutic Target in INI1-Deficient Epithelioid Sarcoma. Cancer Science , (2025); https://doi.org/10.1111/cas.16438.
Abstract
Effective therapeutic strategies for epithelioid sarcoma (EpS), a high-grade soft tissue sarcoma characterized by loss of integrase interactor 1 (INI1), have not yet been developed. The present study therefore investigated the association between INI1 loss and upregulation of the aurora kinase A (AURKA)/polo-like kinase 1 (PLK1)/cell division cycle 25C (CDC25C) axis, as well as the therapeutic relevance of this axis in EpS. Notably, our findings showed that the reintroduction of INI1 in VA-ES-BJ cells significantly reduced proliferation, mitigated tumorigenicity, and negatively regulated the expression of AURKA and its downstream effectors, as well as the activation of PLK1 and CDC25C. These results suggest that INI1 deficiency enhanced EpS growth by upregulating the AURKA/PLK1/CDC25C axis. AURKA silencing using siRNAs inhibited VA-ES-BJ and Asra-EPS cell proliferation by inactivating PLK1 and CDC25C. Alisertib, a selective AURKA inhibitor, exerted markedly greater antiproliferative effects on EpS cells than on normal human dermal fibroblasts, and these effects were dependent on INI1 deficiency. Inhibition of AURKA activity by alisertib induced G2/M cell cycle arrest and apoptosis via the inactivation of AURKA downstream effectors in EpS cells. Alisertib also significantly decreased VA-ES-BJ xenograft tumor growth. Taken together, our findings revealed that INI1 loss in EpS cells enhances the expression of AURKA and its downstream effectors and persistently activates PLK1 and CDC25C mediated by AURKA, making the cells reliant on the AURKA/PLK1/CDC25C axis. Therefore, the AURKA/PLK1/CDC25C axis activated by INI1 deficiency could serve as a novel therapeutic target for this devastating disease.
Publisher
John Wiley and Sons Inc
Source Title
Cancer Science
Date of Issued
2025-01-09
Language
English
Handle URL
https://hdl.handle.net/11094/100350
PISSN
13479032
eISSN
13497006
Relation.isIdenticalTo
DOI (Publisher Version)
https://doi.org/10.1111/cas.16438
Access Rights
open access
CopyRight
This article is licensed under a Creative Commons Attribution 4.0 International License.
oaire:version
Version of Record
Category
学術雑誌論文 Journal Article