Activation of the MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis protects MG-63 osteosarcoma cells against 15d-PGJ2-mediated cell death

Biochemical Pharmacology
Chintan N KoyaniErnst Malle

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 independen...Continue Reading

References

Mar 31, 1989·Biochemical and Biophysical Research Communications·Y Koshihara, M Kawamura
May 9, 1998·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·S KomiyaA Inoue
Dec 3, 1999·Prostaglandins, Leukotrienes, and Essential Fatty Acids·H TokudaT Uematsu
Apr 13, 2001·Medicinal Research Reviews·D S Straus, C K Glass
Oct 2, 2002·FEBS Letters·Doron Ginsberg
Nov 13, 2004·The Journal of Gene Medicine·Olaf J C HellwinkelHartmut Kabisch
May 18, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Pascal O BerberatHelmut Friess
Mar 3, 2007·Apoptosis : an International Journal on Programmed Cell Death·Song JinJia-Guo Zhou
Apr 25, 2007·Biochemical Pharmacology·Rufina SchuligoiAkos Heinemann
Jul 20, 2007·Journal of Neuroinflammation·Zhongmin XiangSteven A Reeves
Jan 12, 2008·Progress in Lipid Research·Hisako HikijiSatoshi Ishii
Feb 28, 2008·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Marianne DurandArtur J de Brum-Fernandes
Sep 6, 2008·Prostaglandins, Leukotrienes, and Essential Fatty Acids·Haruhiko TokudaOsamu Kozawa
May 30, 2009·Nature Reviews. Drug Discovery·Dunyaporn TrachoothamPeng Huang
Jul 4, 2009·Free Radical Biology & Medicine·Emilia KansanenAnna-Liisa Levonen
Nov 20, 2009·Journal of Bone and Mineral Metabolism·Ignazio BarbagalloDavid Asprinio
Apr 8, 2010·Free Radical Research·Geou-Yarh Liou, Peter Storz
Apr 27, 2010·Biochemical and Biophysical Research Communications·Huaqun ChenChaojun Li
Aug 19, 2010·Oxidative Medicine and Cellular Longevity·Asha AcharyaTapas Saha
Nov 30, 2010·The Journal of Biological Chemistry·Karine MathurinJean-Luc Parent
May 28, 2011·International Journal of Oncology·Shinji MiwaHiroyuki Tsuchiya
Jun 15, 2011·DNA Repair·Michaela SemlitschErnst Malle
Apr 17, 2012·Seminars in Cell & Developmental Biology·Hongqiao Zhang, Henry Jay Forman
Sep 22, 2012·Biochimica Et Biophysica Acta·Shelly C Lu
Oct 11, 2012·Frontiers in Physiology·Stephanie B WallAimee Landar
Apr 20, 2013·International Immunopharmacology·Marcelo Henrique NapimogaElizabeth Ferreira Martinez
Nov 10, 2013·Free Radical Biology & Medicine·Hye-Kyung Na, Young-Joon Surh
Apr 8, 2014·Cell Reports·Xiang ChenUNKNOWN St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project
May 13, 2014·Prostaglandins, Leukotrienes, and Essential Fatty Acids·Gen KuroyanagiHaruhiko Tokuda
Feb 24, 2015·Clinica Chimica Acta; International Journal of Clinical Chemistry·Jian ZhangWen-Jun Wang
Jun 30, 2015·Progress in Lipid Research·Alexandrine DuringPierre Hardouin

❮ Previous
Next ❯

Citations

May 21, 2016·Frontiers in Cell and Developmental Biology·Eddie Rodríguez-CarballoFrancesc Ventura
May 10, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Canhong WangCao Li
Oct 25, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Peng-Cheng LiAi-Ming Yu
Nov 30, 2018·Frontiers in Physiology·Chintan N KoyaniDirk von Lewinski
Sep 26, 2017·Molecular Medicine Reports·Hui YeXi-Chun Hu
Sep 15, 2017·Journal of Medicinal Food·Ji Yeon SeoWon Keun Oh
Nov 24, 2020·Metallomics : Integrated Biometal Science·Rui-Feng FanZhen-Yong Wang
Oct 14, 2020·Biochemistry. Biokhimii︠a︡·E V Kalinina, L A Gavriliuk
Jan 16, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jiajun ZhangJingnan Shen
Mar 12, 2021·Cellular Oncology (Dordrecht)·S Mazher HussainEvan S Glazer

❮ Previous
Next ❯

Methods Mentioned

BETA
FCS
protein assay
electrophoresis
PCR
transfection
Assay
flow cytometry
ubiquitination

Software Mentioned

SPSS

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis