NYMC Faculty Publications
Protein Phosphatase 1 Regulatory Subunit 1A Regulates Cell Cycle Progression in Ewing Sarcoma
DOI
10.18632/oncotarget.27571
Journal Title
Oncotarget
First Page
1691
Last Page
1704
Document Type
Article
Publication Date
5-12-2020
Department
Pediatrics
Second Department
Health Behavior and Community Health
Abstract
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.
Recommended Citation
Luo, W., Xu, C., Phillips, S., Gardenswartz, A., Rosenblum, J. M., Ayello, J., Lessnick, S. L., Hao, H., & Cairo, M. S. (2020). Protein Phosphatase 1 Regulatory Subunit 1A Regulates Cell Cycle Progression in Ewing Sarcoma. Oncotarget, 11 (19), 1691-1704. https://doi.org/10.18632/oncotarget.27571