Deubiquitinylase USP47 Promotes RelA Phosphorylation and Survival in Gastric Cancer Cells.
Lara NaghaviMartin SchwalbeAhmed GhanemMichael NaumannPublished in: Biomedicines (2018)
Every year, gastric cancer causes around 819,000 deaths worldwide. The incidence of gastric cancer in the western world is slowly declining, but the prognosis is unpromising. In Germany, the 5-year-survival rate is around 32%, and the average life span after diagnosis is 6 to 9 months. Therapy of gastric cancer patients comprises a gastrectomy and perioperative or adjuvant chemotherapy. However, resistance of gastric cancer cells to these agents is widespread; thus, improved chemotherapeutic approaches are required. Nuclear factor kappa B (NF-κB) transcription factors are associated with anti-apoptosis, carcinogenesis, and chemoresistance, and thus, constitute attractive targets for therapeutic intervention. In immunoblots, we show that ubiquitin specific protease 47 (USP47) promotes β-transducin repeat-containing protein (βTrCP) stability and phosphorylation of RelA. Furthermore, after knockdown of USP47 by RNA interference, we analyzed in gastric cancer cell lines metabolic activity/viability in an MTT assay, and apoptotic cell death by Annexin V staining and poly(ADP-Ribose) polymerase (PARP)-1, caspase 3, and caspase 8 cleavage, respectively. We found that USP47 contributes to cell viability and chemoresistance in NCI-N87 gastric carcinoma cells treated with etoposide and camptothecin. Inhibition of USP47 might be a suitable strategy to downregulate NF-κB activity, and to overcome chemoresistance in gastric cancer.
Keyphrases
- nuclear factor
- cell death
- toll like receptor
- cell cycle arrest
- oxidative stress
- signaling pathway
- transcription factor
- randomized controlled trial
- stem cells
- risk factors
- small molecule
- induced apoptosis
- lps induced
- endoplasmic reticulum stress
- protein kinase
- free survival
- pi k akt
- high throughput
- newly diagnosed
- protein protein
- south africa
- acute kidney injury
- binding protein