2. Academic Validation
  3. Skp2 depletion reduces tumor-initiating properties and promotes apoptosis in synovial sarcoma

Skp2 depletion reduces tumor-initiating properties and promotes apoptosis in synovial sarcoma

  • Transl Oncol. 2020 Oct;13(10):100809. doi: 10.1016/j.tranon.2020.100809.
Jichuan Wang 1,  Kenji Sato 2,  Ed O'Donnell 2,  Amit Singla 2,  Simon Yaguare 2,  Osama Aldahamsheh 2,  Brian Batko 2,  Hasibagan Borjihan 2,  Janet Tingling 2,  Jinghang Zhang 3,  Daniel A Weiser 4,  David M Loeb 4,  Richard Gorlick 5,  Edward L Schwartz 6,  Rui Yang 2,  Xiaolin Zi 7,  Hongling Zhao 8,  David S Geller 2,  Bang H Hoang 9
Affiliations

Affiliations

  • 1 Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Musculoskleletal Tumor Center, Beijing Key Laboratory for Musculoskeletal Tumors, Peking University People's Hospital, Beijing, China.
  • 2 Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.
  • 3 Flow Cytometry Core Facility, Albert Einstein College of Medicine, Bronx, NY.
  • 4 Division of Pediatric Hematology-Oncology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY.
  • 5 Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX.
  • 6 Departments of Medicine (Oncology) and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY.
  • 7 Department of Urology, University of California, Irvine Medical Center, Orange, CA.
  • 8 Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY.
  • 9 Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY. Electronic address: bahoang@montefiore.org.
PMID: 32623326 DOI: 10.1016/j.tranon.2020.100809
Abstract

Synovial sarcoma (SS) is an aggressive soft-tissue Cancer with a poor prognosis and a propensity for local recurrence and distant metastasis. In this study, we investigated whether S phase kinase-associated protein (Skp2) plays an oncogenic role in tumor initiation, progression, and metastasis of SS. Our study revealed that Skp2 is frequently overexpressed in SS specimens and SS18-SSX transgenic mouse tumors, as well as correlated with clinical stages. Next, we identified that genetic depletion of Skp2 reduced mesenchymal and stemness markers, and inhibited the invasive and proliferative capacities of SS cell lines. Furthermore, Skp2 depletion markedly suppressed the growth of SS xenografts tumors. Treatment of SS cell lines with the skp2 inhibitor flavokawain A (FKA) reduced Skp2 expression in a dose-dependent manner and resulted in cell cycle arrest and Apoptosis. FKA also suppressed the invasion and tumor-initiating properties in SS, similar to the effects of Skp2 knockdown. In addition, a combination of FKA and conventional chemotherapy showed a synergistic therapeutic efficacy. Taken together, our results suggest that Skp2 plays an essential role in the biology of SS by promoting the mesenchymal state and Cancer stemness. Given that chemotherapy resistance is often associated with Cancer stemness, strategies of combining Skp2 inhibitors with conventional chemotherapy in SS may be desirable.

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