Activation of the MAPK/Akt/Nrf2-Egr1/HO-1-GCLc axis protects MG-63 osteosarcoma cells against 15d-PGJ(2)-mediated cell death

作者：Koyani Chintan N; Kitz Kerstin; Rossmann Christine; Bernhart Eva; Huber Evelyn; Trummer Christopher; Windischhofer Werner; Sattler Wolfgang; Malle Ernst^*

来源：Biochemical Pharmacology, 2016, 104: 29-41.

DOI：10.1016/j.bcp.2016.01.011

• 15d-PGJ(2)
• Chemotherapy
• PI3K/Akt axis
• Peroxisome proliferator-activated-receptor gamma
• Pro-survival signalling
• ROS
• Tumour protein p53

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-Delta(12,14)-PGJ(2) (15d-PGJ(2), a stable PGD(2) degradation product) on cell death/cell survival pathways in p53-deficient MG-63 OS cells. Our findings show that 15d-PGJ(2) 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-PGJ(2)-mediated reduction of cellular metabolic activity. Activation of cell survival genes including HO-1 and GCLc inhibited 15d-PGJ(2)-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-PGJ(2). The observed 15d-PGJ(2)-mediated signalling events are independent of PGD(2) receptors (DP1 and DP2) and PPAR gamma. In addition, the electrophilic carbon atom C9 is a prerequisite for the observed activity of 15d-PGJ(2). The present data show that the intracellular redox imbalance acted as a node and triggered both death and survival pathways in response to 15d-PGJ(2). 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-PGJ(2)-mediated apoptosis.

• 出版日期2016-3-15