title: Cytotoxic effects of 15d-PGJ2 against osteosarcoma through ROS-mediated AKT and cell cycle inhibition.
abstract: 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.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chueh-Chuan
authors.initials: CC
authors.lastname: Yen
authors.forename: Chung-Der
authors.initials: CD
authors.lastname: Hsiao
authors.forename: Wei-Ming
authors.initials: WM
authors.lastname: Chen
authors.forename: Yao-Shan
authors.initials: YS
authors.lastname: Wen
authors.forename: Yung-Chan
authors.initials: YC
authors.lastname: Lin
authors.forename: Ting-Wei
authors.initials: TW
authors.lastname: Chang
authors.forename: Fang-Yi
authors.initials: FY
authors.lastname: Yao
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
authors.forename: Jir-You
authors.initials: JY
authors.lastname: Wang
authors.forename: Jen-Hwey
authors.initials: JH
authors.lastname: Chiu
authors.forename: Hsei-Wei
authors.initials: HW
authors.lastname: Wang
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Lin
authors.forename: Tain-Hsiung
authors.initials: TH
authors.lastname: Chen
authors.forename: Paul Chih-Hsueh
authors.initials: PC
authors.lastname: Chen
authors.forename: Chien-Lin
authors.initials: CL
authors.lastname: Liu
authors.forename: Cheng-Hwai
authors.initials: CH
authors.lastname: Tzeng
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D015230:Prostaglandin D2; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D000097869:Polo-Like Kinase 1; C097240:15-deoxy-delta(12,14)-prostaglandin J2