Saban Research Institute at Children's Hospital Los Angeles, Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Pediatrics, Los Angeles, California, 90027, USA.
Saban Research Institute at Children's Hospital Los Angeles, Cellular Imaging Core, Los Angeles, California, 90027, USA.
Sci Rep. 2017 Apr 11;7(1):835. doi: 10.1038/s41598-017-00947-6.
Phosphotyrosine Interaction Domain containing 1 (PID1; NYGGF4) inhibits growth of medulloblastoma, glioblastoma and atypical teratoid rhabdoid tumor cell lines. PID1 tumor mRNA levels are highly correlated with longer survival in medulloblastoma and glioma patients, suggesting their tumors may have been more sensitive to therapy. We hypothesized that PID1 sensitizes brain tumors to therapy. We found that PID1 increased the apoptosis induced by cisplatin and etoposide in medulloblastoma and glioblastoma cell lines. PID1 siRNA diminished cisplatin-induced apoptosis, suggesting that PID1 is required for cisplatin-induced apoptosis. Etoposide and cisplatin increased NFκB promoter reporter activity and etoposide induced nuclear translocation of NFκB. Etoposide also increased PID1 promoter reporter activity, PID1 mRNA, and PID1 protein, which were diminished by NFκB inhibitors JSH-23 and Bay117082. However, while cisplatin increased PID1 mRNA, it decreased PID1 protein. This decrease in PID1 protein was mitigated by the proteasome inhibitor, bortezomib, suggesting that cisplatin induced proteasome dependent degradation of PID1. These data demonstrate for the first time that etoposide- and cisplatin-induced apoptosis in medulloblastoma and glioblastoma cell lines is mediated in part by PID1, involves NFκB, and may be regulated by proteasomal degradation. This suggests that PID1 may contribute to responsiveness to chemotherapy.
磷酸酪氨酸相互作用结构域包含蛋白 1（PID1；NYGGF4）抑制髓母细胞瘤、神经胶质瘤和非典型畸胎样横纹肌样肿瘤细胞系的生长。PID1 肿瘤 mRNA 水平与髓母细胞瘤和神经胶质瘤患者的生存时间延长高度相关，这表明他们的肿瘤可能对治疗更为敏感。我们假设 PID1 使脑肿瘤对治疗更敏感。我们发现 PID1 增加了顺铂和依托泊苷诱导的髓母细胞瘤和神经胶质瘤细胞系的细胞凋亡。PID1 siRNA 减少了顺铂诱导的细胞凋亡，表明 PID1 是顺铂诱导的细胞凋亡所必需的。依托泊苷和顺铂增加了 NFκB 启动子报告基因的活性，并且依托泊苷诱导了 NFκB 的核转位。依托泊苷还增加了 PID1 启动子报告基因的活性、PID1 mRNA 和 PID1 蛋白，NFκB 抑制剂 JSH-23 和 Bay117082 则降低了这些表达。然而，虽然顺铂增加了 PID1 mRNA，但它降低了 PID1 蛋白。这种 PID1 蛋白的减少被蛋白酶体抑制剂硼替佐米缓解，表明顺铂诱导了 PID1 的蛋白酶体依赖性降解。这些数据首次表明，依托泊苷和顺铂诱导的髓母细胞瘤和神经胶质瘤细胞系的细胞凋亡部分由 PID1 介导，涉及 NFκB，并且可能受到蛋白酶体降解的调节。这表明 PID1 可能有助于对化疗的反应性。
