Abstract
Platinum chemotherapeutics are widely used to treat solid malignant tumors, including gastric cancer (GC). Drug resistance to platinum compounds may result in cancer relapse and decreased survival. The identification and development of novel agents to reactivate apoptosis pathways in platinum-resistant cancer cells is therefore necessary. Here we report that cisplatin-resistant human GC cells (BGC823/DDP and SGC7901/DDP) but not their parental cells (BGC823 and SGC7901) exhibit high sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a result of overexpression of death receptor 4 (DR4). Furthermore, we found that JWA, a molecule that promotes cisplatin-induced apoptosis in GC cells, suppressed TRAIL-induced apoptosis via negative regulation of DR4. Mechanistically, JWA promoted the ubiquitination of DR4 at K273 via upregulation of the ubiquitin ligase membrane-associated RING-CH-8 (MARCH8). In human GC tissues, JWA and DR4 protein levels were negatively correlated. Thus TRAIL may serve as an auxiliary treatment for cisplatin-resistant GC, and JWA may be a potential predictive marker of TRAIL sensitivity and may improve personalized therapeutics for treating human GC.
Highlights
Gastric cancer (GC) is the third leading cause of death resulting from cancer worldwide.[1,2,3] Almost 50% of all GC cases are diagnosed in China.[1,4] Platinum-based chemotherapeutics remain the cornerstone of therapy for cancers, including GC.[5,6] innate or acquired resistance to platinum is very common in the treatment of solid tumors,[7] and resistance to platinum agents, such as cisplatin (DDP), may be accompanied by cross-tolerance to DNA-damaging drugs, for example, gemcitabine, etoposide and 5-fluorouracil.[5]
To investigate whether death receptor (DR) are involved in cisplatin resistance in human GC cells, DR expression patterns (DR4/DR5, tumor necrosis factor receptor 1 (TNFR1) and Fas) in two human GC cell lines (BGC823, SGC7901) and their cisplatinresistant variants were analyzed
These results indicated that cisplatin-resistant GC cells may be sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), because death receptor 4 (DR4) is a DR for TRAIL
Summary
Gastric cancer (GC) is the third leading cause of death resulting from cancer worldwide.[1,2,3] Almost 50% of all GC cases are diagnosed in China.[1,4] Platinum-based chemotherapeutics remain the cornerstone of therapy for cancers, including GC.[5,6] innate or acquired resistance to platinum is very common in the treatment of solid tumors,[7] and resistance to platinum agents, such as cisplatin (DDP), may be accompanied by cross-tolerance to DNA-damaging drugs, for example, gemcitabine, etoposide and 5-fluorouracil.[5]. Beyond the mitochondrial apoptotic pathway, the death receptor (DR) pathway triggers apoptotic cell death and is involved in classical ligand–cell surface receptor interactions.[12]
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