title: Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cells metastasis by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways.
abstract: Zoledronate is a standard treatment for preventing skeletal complications of osteoporosis and some types of cancer associated with bone metastases, but we little know whether the effect of zoledronate on metastasis of osteosarcoma. Here, we investigated the inhibitory effects of zoledronate on cell viability, motility, migration and invasion of 4 osteosarcoma cell lines (Saos2, MG-63, HOS and U2OS) by affecting cell morphology, epithelial-mesenchymal transition (EMT) and cytoskeletal organization as well as induction of E-cadherin and reduction of N-cadherin with activation of transcription factors Slug and Twist, especially in U2OS cells. Zoledronate decreased JNK and p38 phosphorylation and upper streams of focal adhesion kinase (FAK) and Src to suppress the motility, invasiveness and migration of U2OS cells. In addition to zoledronate-inhibited Rho A and Cdc42 membrane translocation and GTPγS activities, the anti-metastatic effects in U2OS cells including inhibition of adhesion were reversed by geranylgeraniol, but not farnesol. In conclusion, Zoledronate blocks geranylgeranylation not farnesylation to suppress human osteosarcoma U2OS cell-matrix and cell-cell interactions, migration potential, the invasive activity, and the adhesive ability by EMT via Rho A activation and FAK-inhibited JNK and p38 pathways.
authors: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors: Hsin-Lin
authors: HL
authors: Cheng
authors: Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors: Chiao-Wen
authors: CW
authors: Lin
authors: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors: Jia-Sin
authors: JS
authors: Yang
authors: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.|Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan.
authors: Ming-Ju
authors: MJ
authors: Hsieh
authors: Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
authors: Shun-Fa
authors: SF
authors: Yang
authors: Department of Orthopedics, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.|School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
authors: Ko-Hsiu
authors: KH
authors: Lu
mesh_terms: D001692:Biological Transport / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005204:Farnesol / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D010024:Osteoporosis / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D012516:Osteosarcoma / Q000188:drug therapy / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D054876:Prenylation / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000378:metabolism; D000077211:Zoledronic Acid; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; D015820:Cadherins; D004164:Diphosphonates; D004224:Diterpenes; D007093:Imidazoles; D009687:Nuclear Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D005204:Farnesol; D000077211:Zoledronic Acid; C017338:geranylgeraniol; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src); D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein
keywords: Rho A; U2OS; geranylgeranylation; metastasis; zoledronate