Luo, Wen, Xu, Changxin, Phillips, Sarah, Gardenswartz, Aliza, Rosenblum, Jeremy M., Ayello, Janet, Lessnick, Stephen L., Hao, Huaixiang and Cairo, Mitchell S. (2020) Protein phosphatase 1 regulatory subunit 1A regulates cell cycle progression in Ewing sarcoma. Oncotarget, 11 (19). ISSN 1949-2553

Abstract

Introduction: We recently identified protein phosphatase 1 regulatory subunit 1A (PPP1R1A) as oneof the EWS/FLI core targets that promotes tumor growth and metastasis in Ewing sarcoma (ES), an aggressive pediatric bone and soft tissue tumor. In the current study, we seek to further define the role of PPP1R1A in ES and identify rational combinatorial therapy with improved and specific efficacy in treating primary and metastatic ES.

Experimental design: We evaluated ES cell proliferation and cell cycle progression in control and PPP1R1A depleted ES cells. PPP1R1A regulation of cell cycle modulators was analyzed to characterize the underlying mechanism of PPP1R1A mediated cell cycle control. The effects of combination of PPP1R1A and IGF-1R inhibition on ES cell viability and migration in vitro as well as tumor growth and metastasis in an orthotopic xenograft mouse model were investigated.

Results: PPP1R1A regulates ES cell cycle in G1/S phase by down-regulating cell cycle inhibitors p21Cip1 and p27Kip1 which results in Rb protein hyperphosphorylation and by promoting normal transcription of replication-dependent histone genes. Furthermore, the combination of PPP1R1A and IGF-1R inhibition induced a synergistic/additive effect on decreasing cell proliferation and migration in vitro and xenograft tumor growth and metastasis in vivo.

Conclusions: 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.

Item Type:	Article
Date Deposited:	02 Jun 2020 00:45
Last Modified:	02 Jun 2020 00:45
URI:	https://oak.novartis.com/id/eprint/41620