Wang Q, Chen Q, Zhu L, Chen M, Xu W, Panday S, Wang Z, Li A, Røe O D, Chen R, Wang S, Zhang R, Zhou J
Department of Molecular Cell Biology and Toxicology, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, China.
Oncogenesis. 2017 Jul 3;6(7):e353. doi: 10.1038/oncsis.2017.57.
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.
铂类化疗药物被广泛用于治疗实体恶性肿瘤，包括胃癌（GC）。对铂类化合物的耐药性可能导致癌症复发和生存率降低。因此，识别和开发新型药物以重新激活铂耐药癌细胞中的凋亡途径是必要的。在此我们报告，顺铂耐药的人胃癌细胞（BGC823/DDP和SGC7901/DDP）而非其亲本细胞（BGC823和SGC7901）由于死亡受体4（DR4）的过表达而对肿瘤坏死因子相关凋亡诱导配体（TRAIL）表现出高敏感性。此外，我们发现JWA，一种促进胃癌细胞中顺铂诱导凋亡的分子，通过对DR4的负调控抑制TRAIL诱导的凋亡。机制上，JWA通过上调泛素连接酶膜相关RING-CH-8（MARCH8）促进DR4在K273处的泛素化。在人胃癌组织中，JWA和DR4蛋白水平呈负相关。因此，TRAIL可作为顺铂耐药胃癌的辅助治疗，而JWA可能是TRAIL敏感性的潜在预测标志物，并可能改善人胃癌的个性化治疗。
