Work

PPP2R1A regulated by PAX3/FOXO1 fusion contributes to the acquisition of aggressive behavior in PAX3/FOXO1-positive alveolar rhabdomyosarcoma

Year: 2018

Type: article

Abstract: // Keisuke Akaike 1, 2, * , Yoshiyuki Suehara 1, * , Shinji Kohsaka 3 , Takuo Hayashi 2 , Yu Tanabe 1 , Saiko Kazuno 4 , Kenta Mukaihara 1 , Midori Toda-Ishii 1 , Taisei Kurihara 1 , Youngji Kim 1 , Taketo Okubo 1 , Yasuhide Hayashi 5 , Kazuya Takamochi 6 , Fumiyuki Takahashi 7 , Kazuo Kaneko 2 , Marc Ladanyi 8 and Tsuyoshi Saito 2 1 Department of Orthopedic Surgery, Juntendo University School of Medicine, Tokyo, Japan 2 Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan 3 Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 4 Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan 5 Department of Hematology/Oncology, Gunma Children’s Medical Center, Shibukawa, Gunma, Japan 6 Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan 7 Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan 8 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA * These authors contributed equally to this work Correspondence to: Yoshiyuki Suehara, email: [email protected] Tsuyoshi Saito, email: [email protected] Keywords: alveolar rhabdomyosarcoma (ARMS); proteomics; PAX3/FOXO1; PPP2R1A; PP2A Received: January 30, 2018 Accepted: April 28, 2018 Published: May 18, 2018 ABSTRACT To better characterize the oncogenic role of the PAX3-FOXO1 fusion protein in the acquisition of aggressive behavior in ARMS, we employed a proteomic approach using a PAX3-FOXO1 knockdown system in ARMS cell lines. This approach revealed a protein list consisting of 107 consistently upregulated and 114 consistently downregulated proteins that were expected to be regulated by PAX3-FOXO1 fusion protein. Furthermore, we identified 16 upregulated and 17 downregulated critical proteins based on a data-mining analysis. We also evaluated the function of PPP2R1A in ARMS cells. The PPP2R1A expression was upregulated at both the mRNA and protein levels by PAX3-FOXO1 silencing. The silencing of PPP2R1A significantly increased the cell growth of all four ARMS cells, suggesting that PPP2R1A still has a tumor suppressive function in ARMS cells; however, the native expression of PPP2R1A was low in the presence of PAX3-FOXO1. In addition, the activation of PP2A—part of which was encoded by PPP2R1A —by FTY720 treatment in ARMS cell lines inhibited cell growth. On the human phospho-kinase array analysis of 46 specific Ser/Thr or Tyr phosphorylation sites on 39 selected proteins, eNOS, AKT1/2/3, RSK1/2/3 and STAT3 phosphorylation were decreased by FTY-720 treatment. These findings suggest that PPP2R1A is a negatively regulated by PAX3-FOXO1 in ARMS. The activation of PP2A—probably in combination with kinase inhibitors—may represent a therapeutic target in ARMS. We believe that the protein expression profile associated with PAX3-FOXO1 would be valuable for discovering new therapeutic targets in ARMS.

Source: Oncotarget

DOI: 10.18632/oncotarget.25392