Abstract
BackgroundPancreatic 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.MethodsDrug 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).ResultsThe 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.ConclusionsFBP1 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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumor types worldwide
FBP1 is responsible for modulating the bromodomain and extraterminal domain (BET) inhibitor sensitivity in PDAC The FBP1 is a well-known tumor suppressor gene that exhibits low expression or loss of expression in many types of solid tumors [20,21,22]
We showed that JQ1 treatment increased FBP1 protein level (Fig. 2a and e) but not the mRNA level (Fig. 2b and f ) in dose-and time- dependent manners in both PANC-1 and SW1990 pancreatic cancer cells
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumor types worldwide. BET inhibitors display anti-tumor activity in pancreatic cancer, the cells often develop resistance after a longterm treatment and the underlying molecular basis is not fully understood. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumor types worldwide and is characterized by a highly invasive and metastatic phenotype [1]. The occurrence and mortality of PDAC remain largely unchanged after decades of studies. BET proteins usually are overexpressed in pancreatic cancer and involved in promoting tumor cell proliferation and metastasis [4]. BET inhibitors have been shown to display anti-tumor activity in KRAS-driven cancers, such as pancreatic ductal adenocarcinoma and non-small cell lung cancer [4, 5]
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