FBP1 缺失通过削弱胰腺导管腺癌中的 c-Myc 表达导致 BET 抑制剂耐药。
FBP1 loss contributes to BET inhibitors resistance by undermining c-Myc expression in pancreatic ductal adenocarcinoma.
机构信息
Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Digestive Surgical Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
出版信息
J Exp Clin Cancer Res. 2018 Sep 10;37(1):224. doi: 10.1186/s13046-018-0888-y.
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumor types worldwide. BET inhibitors display anti-tumor activity in pancreatic cancer, however the cells often develop resistance after a long-term treatment and the underlying molecular basis is not fully understood.
METHODS
Drug screening assay in Fructose-1, 6-biphosphatase (FBP1) knockdown or overexpressing pancreatic cancer cells was performed. Tumor cell motility, FBP1 protein and mRNA changes were investigated after BET inhibitors treatment. The interaction between TRIM28 and FBP1 after BET inhibitors treatment was examined by Co-immunoprecipitation (IP) and GST pull-down. The relationship between FBP1 and c-Myc was examined by western blot, RT-qPCR and immunohistochemistry (IHC).
RESULTS
The expression of FBP1 protein increased the sensitivity of pancreatic cancer cells to JQ1. Furthermore, we showed that JQ1 stabilized FBP1 protein level by disrupting the interaction between FBP1 and TRIM28 in pancreatic cancer cells. Moreover, we demonstrated that FBP1 promoted c-Myc degradation through disrupting the ERK-c-Myc axis.
CONCLUSIONS
FBP1 modulates the sensitivity of pancreatic cancer cells to BET inhibitors by decreasing the expression of c-Myc. These findings highlight FBP1 could be used as a therapeutic niche for patient-tailored therapies.
背景
胰腺导管腺癌（PDAC）是全球最致命的肿瘤类型之一。BET 抑制剂在胰腺癌中显示出抗肿瘤活性，然而，细胞在长期治疗后常常会产生耐药性，其潜在的分子基础尚不完全清楚。
方法
在果糖-1,6-二磷酸酶（FBP1）敲低或过表达的胰腺癌细胞中进行药物筛选实验。研究 BET 抑制剂处理后肿瘤细胞迁移、FBP1 蛋白和 mRNA 的变化。用 Co-免疫沉淀（Co-IP）和 GST 下拉实验检测 BET 抑制剂处理后 TRIM28 和 FBP1 之间的相互作用。用 Western blot、RT-qPCR 和免疫组化（IHC）检测 FBP1 和 c-Myc 之间的关系。
结果
FBP1 蛋白的表达增加了胰腺癌细胞对 JQ1 的敏感性。此外，我们表明 JQ1 通过破坏胰腺癌细胞中 FBP1 和 TRIM28 之间的相互作用稳定了 FBP1 蛋白水平。此外，我们证明 FBP1 通过破坏 ERK-c-Myc 轴促进 c-Myc 降解。
结论
FBP1 通过降低 c-Myc 的表达来调节胰腺癌细胞对 BET 抑制剂的敏感性。这些发现强调了 FBP1 可以作为患者个体化治疗的治疗靶点。
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