Cytotoxic effects of 15d-PGJ2 against osteosarcoma through ROS-mediated AKT and cell cycle inhibition
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Chueh-Chuan Yen1,2,3,*, Chung-Der Hsiao4,*, Wei-Ming Chen2,3,5, Yao-Shan Wen1, Yung-Chan Lin1, Ting-Wei Chang1, Fang-Yi Yao1, Shih-Chieh Hung3,5,6,7, Jir-You Wang3,5,6, Jen-Hwey Chiu8,9, Hsei-Wei Wang7,10,11, Chi-Hung Lin10,11, Tain-Hsiung Chen2,3,5, Paul Chih-Hsueh Chen2,3,12, Chien-Lin Liu2,3,5, Cheng-Hwai Tzeng1,2, and Jonathan A. Fletcher13
1 Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
2 National Yang-Ming University School of Medicine, Taipei, Taiwan
3 Therapeutical and Research Center of Musculoskeletal Tumor, Taipei Veterans General Hospital, Taipei, Taiwan
4 Epidermal Stem Cell Lab, Department of Bioscience Technology, Chung Yuan Christian University, Chung-Li, Taiwan
5 Department of Orthopedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan
6 Stem Cell Laboratory, Department of Medical Research and Education, Taipei Veterans General Hospital, and Institute of Pharmacology, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
7 Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
8 Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan
9 Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, and Department of Surgery, Cheng-Hsin General Hospital, Taipei, Taiwan
10 Institute of Microbiology and Immunology, and Cancer Research Center & Genome Research Center, National Yang-Ming University, Taipei, Taiwan
11 Department of Education and Research, Taipei City Hospital, Taipei, Taiwan
12 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
13 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, U.S.A
* These authors contributed equally to this study.
Chueh-Chuan Yen, email:
Keywords: 15d-PGJ2, AKT, PLK1, osteosarcoma
Received: December 14, 2013 Accepted: January 19, 2014 Published:January 21, 2014
Polo-like kinase 1 (PLK1), a critical cell cycle regulator, has been identified as a potential target in osteosarcoma (OS). 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), a prostaglandin derivative, has shown its anti-tumor activity by inducing apoptosis through reactive oxygen species (ROS)-mediated inactivation of v-akt, a murine thymoma viral oncogene homolog, (AKT) in cancer cells. In the study analyzing its effects on arthritis, 15d-PGJ2 mediated shear-induced chondrocyte apoptosis via protein kinase A (PKA)-dependent regulation of PLK1. In this study, the cytotoxic effect and mechanism underlying 15d-PGJ2 effects against OS were explored using OS cell lines. 15d-PGJ2 induced significant G2/M arrest, and exerted time- and dose-dependent cytotoxic effects against all OS cell lines. Western blot analysis showed that both AKT and PKA-PLK1 were down-regulated in OS cell lines after treatment with 15d-PGJ2. In addition, transfection of constitutively active AKT or PLK1 partially rescued cells from 15d-PGJ2-induced apoptosis, suggesting crucial roles for both pathways in the anti-cancer effects of 15d-PGJ2. Moreover, ROS generation was found treatment with 15d-PGJ2, and its cytotoxic effect could be reversed with N-acetyl-l-cysteine. Furthermore, inhibition of JNK partially rescued 15d-PGJ2 cytotoxicity. Thus, ROS-mediated JNK activation may contribute to apoptosis through down-regulation of the p-Akt and PKA-PLK1 pathways. 15d-PGJ2 is a potential therapeutic agent for OS, exerting cytotoxicity mediated through both AKT and PKA-PLK1 inhibition, and these results form the basis for further analysis of its role in animal studies and clinical applications.
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