Protein phosphatase 1 regulatory subunit 1A regulates cell cycle progression in Ewing sarcoma
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Wen Luo1,2, Changxin Xu3, Sarah Phillips4, Aliza Gardenswartz1, Jeremy M. Rosenblum1, Janet Ayello1, Stephen L. Lessnick5, Huai-Xiang Hao6 and Mitchell S. Cairo1,2,4,7,8
1 Department of Pediatrics, New York Medical College, Valhalla, NY, USA
2 Department of Pathology, New York Medical College, Valhalla, NY, USA
3 James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA
4 Department of Medicine, New York Medical College, Valhalla, NY, USA
5 Nationwide Children’s Hospital, Columbus, OH, USA
6 Novartis Institutes for BioMedical Research, Cambridge, MA, USA
7 Department of Immunology and Microbiology, New York Medical College, Valhalla, NY, USA
8 Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA
|Mitchell S. Cairo,||email:||Mitchell_Cairo@nymc.edu|
Keywords: PPP1R1A; cell cycle control; IGF-1R; metastasis; Ewing sarcoma
Received: January 15, 2020 Accepted: April 10, 2020 Published: May 12, 2020
Ewing sarcoma (ES) is a malignant pediatric bone and soft tissue tumor. Patients with metastatic ES have a dismal outcome which has not been improved in decades. The major challenge in the treatment of metastatic ES is the lack of specific targets and rational combinatorial therapy. We recently found that protein phosphatase 1 regulatory subunit 1A (PPP1R1A) is specifically highly expressed in ES and promotes tumor growth and metastasis in ES. In the current investigation, we show that PPP1R1A regulates ES cell cycle progression in G1/S phase by down-regulating cell cycle inhibitors p21Cip1 and p27Kip1, which leads to retinoblastoma (Rb) protein hyperphosphorylation. In addition, we show that PPP1R1A promotes normal transcription of histone genes during cell cycle progression. Importantly, we demonstrate a synergistic/additive effect of the combinatorial therapy of PPP1R1A and insulin-like growth factor 1 receptor (IGF-1R) inhibition on decreasing ES cell proliferation and migration in vitro and limiting xenograft tumor growth and metastasis in vivo. Taken together, our findings suggest a role of PPP1R1A as an ES specific cell cycle modulator and that simultaneous targeting of PPP1R1A and IGF-1R pathways is a promising specific and effective strategy to treat both primary and metastatic ES.
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