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Koyani, CN; Kitz, K; Rossmann, C; Bernhart, E; Huber, E; Trummer, C; Windischhofer, W; Sattler, W; Malle, E.
Activation of the MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis protects MG-63 osteosarcoma cells against 15d-PGJ2-mediated cell death.
Biochem Pharmacol. 2016; 104:29-41 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Bernhart Eva Maria
Huber Evelyn
Kitz Kerstin
Koyani Chintan Navinchandra
Malle Ernst
Rossmann Christine Renate
Sattler Wolfgang
Trummer Christopher
Windischhofer Werner
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Number of Figures: 11
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Abstract:
Despite considerable efforts to improve treatment modalities for osteosarcoma (OS), patient survival remains poor mainly due to pro-survival pathways in OS cells. Among others, prostaglandins (PGs) are the potent regulators of bone homoeostasis and OS pathophysiology. Therefore, the present study aimed to elucidate the impact of 15-deoxy-Δ(12,14)-PGJ2 (15d-PGJ2, a stable PGD2 degradation product) on cell death/cell survival pathways in p53-deficient MG-63 OS cells. Our findings show that 15d-PGJ2 induces generation of reactive oxygen species that promote p38 MAPK activation and subsequent Akt phosphorylation. This pathway induced nuclear expression of Nrf2 and Egr1, and increased transcription of haem oxygenase-1 (HO-1) and the catalytic subunit of glutamate cysteine ligase (GCLc), catalysing the first step in GSH synthesis. Silencing of Nrf2, Egr1 and HO-1 significantly elevated 15d-PGJ2-mediated reduction of cellular metabolic activity. Activation of cell survival genes including HO-1 and GCLc inhibited 15d-PGJ2-induced cleavage of pro-caspase-3 and PARP. Annexin V/propidium iodide staining showed an increase in early/late apoptotic cells in response to 15d-PGJ2. The observed 15d-PGJ2-mediated signalling events are independent of PGD2 receptors (DP1 and DP2) and PPARγ. In addition, the electrophilic carbon atom C9 is a prerequisite for the observed activity of 15d-PGJ2. The present data show that the intracellular redox imbalance acted as a node and triggered both death and survival pathways in response to 15d-PGJ2. Pharmacological or genetic interference of the pro-survival pathway, the p38 MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis, sensitizes MG-63 cells towards 15d-PGJ2-mediated apoptosis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Find related publications in this database (using NLM MeSH Indexing)
Apoptosis - drug effects
Catalytic Domain -
Cell Line, Tumor -
Cell Survival - drug effects
Early Growth Response Protein 1 - genetics Early Growth Response Protein 1 - metabolism
Gene Silencing -
Glutamate-Cysteine Ligase - genetics Glutamate-Cysteine Ligase - metabolism
Heme Oxygenase-1 - genetics Heme Oxygenase-1 - metabolism
Humans -
Mitogen-Activated Protein Kinases - genetics Mitogen-Activated Protein Kinases - metabolism
NF-E2-Related Factor 2 - genetics NF-E2-Related Factor 2 - metabolism
Osteoblasts - drug effects Osteoblasts - metabolism Osteoblasts - pathology
Osteosarcoma - metabolism Osteosarcoma - pathology
Oxidation-Reduction -
Phosphorylation -
Prostaglandin D2 - analogs & derivatives Prostaglandin D2 - pharmacology
Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism
Reactive Oxygen Species - metabolism
Signal Transduction -

Find related publications in this database (Keywords)
15d-PGJ(2)
Chemotherapy
PI3K/Akt axis
Peroxisome proliferator-activated-receptor gamma
Pro-survival signalling
ROS
Tumour protein p53
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