Abstract
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.
Highlights
With 1.3 million incident cases and 819,000 deaths recorded globally, gastric cancer was the fifth most common malignancy, and the third leading cause of cancer deaths in 2015 [1].Surgical gastrectomy remains the only curative therapy
We found that ubiquitin specific protease 47 (USP47) contributes to cell viability and chemoresistance in NCI-N87 gastric carcinoma cells treated with etoposide and camptothecin
We identified the ubiquitin specific protease 47 (USP47), that was previously shown to be essential for the proliferation of gastric carcinomas [19]
Summary
With 1.3 million incident cases and 819,000 deaths recorded globally, gastric cancer was the fifth most common malignancy, and the third leading cause of cancer deaths in 2015 [1]. Because the NF-κB pathway constitutes an attractive target for therapeutic intervention in gastric cancer [5,18], we performed an siRNA screen aiming to identify potential DUB targets that are essential for NF-κB activity. As one such target, we identified the ubiquitin specific protease 47 (USP47), that was previously shown to be essential for the proliferation of gastric carcinomas [19]. We addressed the molecular details of NF-κB regulation using USP47, and examined the viability of USP47 as a promising target for drug intervention to enhance the action of current drugs, and to overcome chemoresistance in gastric cancer cells. Targeting of USP47 represents a suitable strategy to overcome drug resistance in gastric carcinomas
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