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Targeted inhibition of SCFSKP2 confers anti-tumor activities resulting in a survival benefit in osteosarcoma.
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.
Afiliación
  • Wang J; Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Ferrena A; Musculoskleletal Tumor Center, Beijing Key Laboratory for Musculoskeletal Tumors, Peking University People's Hospital, Beijing, China.
  • Zhang R; Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Singh S; Institute for Clinical and Translational Research, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Viscarret V; Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Al-Harden W; Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Aldahamsheh O; Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Borjihan H; Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Singla A; Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Yaguare S; Orthopedic Department, Al-Balqa Applied University, As-Salt, Jordan.
  • Tingling J; Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Zi X; Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Lo Y; Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Gorlick R; Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Schwartz EL; Department of Urology, University of California, Irvine Medical Center, Orange, CA, USA.
  • Zhao H; Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Yang R; Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Geller DS; Departments of Oncology, Molecular Pharmacology, and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Zheng D; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • Hoang BH; Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
Oncogene ; 43(13): 962-975, 2024 Mar.
Article en En | MEDLINE | ID: mdl-38355807
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, RB1 and TP53 have been shown to be the most commonly inactivated tumor suppressors in OS. We previously generated a mouse model with a double knockout (DKO) of Rb1 and Trp53 within 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 SCFSKP2 complex. 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-SKP2 triple-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 SKP2 also 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Óseas / Osteosarcoma Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Óseas / Osteosarcoma Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido