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Targeted inhibition of SCFSKP2confers anti-tumor activities resulting in a survival benefit in osteosarcoma

Authors :
Wang, Jichuan
Ferrena, Alexander
Zhang, Ranxin
Singh, Swapnil
Viscarret, Valentina
Al-Harden, Waleed
Aldahamsheh, Osama
Borjihan, Hasibagan
Singla, Amit
Yaguare, Simon
Tingling, Janet
Zi, Xiaolin
Lo, Yungtai
Gorlick, Richard
Schwartz, Edward L.
Zhao, Hongling
Yang, Rui
Geller, David S.
Zheng, Deyou
Hoang, Bang H.
Source :
Oncogene; March 2024, Vol. 43 Issue: 13 p962-975, 14p
Publication Year :
2024

Abstract

Osteosarcoma(OS) is a highly aggressive bone cancer for which treatment has remained essentially unchanged for decades. Although OS is characterized by extensive genomic heterogeneity and instability, RB1and TP53have been shown to be the most commonly inactivated tumor suppressors in OS. We previously generated a mouse model with a double knockout (DKO) of Rb1and Trp53within cells of the osteoblastic lineage, which largely recapitulates human OS with nearly complete penetrance. SKP2 is a repression target of pRb and serves as a substrate recruiting subunit of the SCFSKP2complex. In addition, SKP2 plays a central role in regulating the cell cycle by ubiquitinating and promoting the degradation of p27. We previously reported the DKOAA transgenic model, which harbored a knock-in mutation in p27 that impaired its binding to SKP2. Here, we generated a novel p53-Rb1-SKP2triple-knockout model (TKO) to examine SKP2 function and its potential as a therapeutic target in OS. First, we observed that OS tumorigenesis was significantly delayed in TKO mice and their overall survival was markedly improved. In addition, the loss of SKP2also promoted an apoptotic microenvironment and reduced the stemness of DKO tumors. Furthermore, we found that small-molecule inhibitors of SKP2 exhibited anti-tumor activities in vivo and in OS organoids as well as synergistic effects when combined with a standard chemotherapeutic agent. Taken together, our results suggest that SKP2 inhibitors may reduce the stemness plasticity of OS and should be leveraged as next-generation adjuvants in this cancer.

Details

Language :
English
ISSN :
09509232 and 14765594
Volume :
43
Issue :
13
Database :
Supplemental Index
Journal :
Oncogene
Publication Type :
Periodical
Accession number :
ejs65499287
Full Text :
https://doi.org/10.1038/s41388-024-02942-4