Abstract
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) signaling have been shown to be dysregulated in multiple cancer types. Glucose regulatory protein 78 (GRP78), the master regulator of the UPR, plays a role in proliferation, invasion, and metastasis in cancer. Cancer stem cells (CSCs) make up a crucial component of the tumor heterogeneity in pancreatic cancer, as well as other cancers. “Stemness” in pancreatic cancer defines a population of cells within the tumor that have increased therapeutic resistance as well as survival advantage. In the current study, we investigated how GRP78 was responsible for maintaining “stemness” in pancreatic cancer thereby contributing to its aggressive biology. We determined that GRP78 downregulation decreased clonogenicity and self-renewal properties in pancreatic cancer cell lines in vitro. In vivo studies resulted in delayed tumor initiation frequency, as well as smaller tumor volume in the shGRP78 groups. Additionally, downregulation of GRP78 resulted in dysregulated fatty acid metabolism in pancreatic tumors as well as the cells. Further, our results showed that shGRP78 dysregulates multiple transcriptomic and proteomic pathways that involve DNA damage, oxidative stress, and cell death, that were reversed upon treatment with a ROS inhibitor, N-acetylcysteine. This study thus demonstrates for the first time that the heightened UPR in pancreatic cancer may be responsible for maintenance of the “stemness” properties in these cells that are attributed to aggressive properties like chemoresistance and metastasis.
Highlights
Pancreatic cancer is a devastating disease with an estimate that 55,440 people will be diagnosed, of which 44,330 people will die in the United States in 2018 alone[1]
Downregulation of Glucose regulatory protein 78 (GRP78) in pancreatic cancer cells affects metabolic pathways regulating survival In order to elucidate the role that GRP78 plays in addition to unfolded protein response and regulation of Endoplasmic reticulum (ER) stress in pancreatic cancer, we constructed a sgGRP78 clonal cell line and conducted a transcriptomic analysis of our shGRP78 cells versus controls
We found a number of genes were significantly deregulated in our shGRP78 group (Fig. 1a)
Summary
Pancreatic cancer is a devastating disease with an estimate that 55,440 people will be diagnosed, of which 44,330 people will die in the United States in 2018 alone[1]. Compared with the 20 most prevalent cancers in the United States, pancreatic cancer is the only type that has a 5-year survival rate of
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