TY - JOUR
T1 - ER stress sensor, glucose regulatory protein 78 (GRP78) regulates redox status in pancreatic cancer thereby maintaining “stemness”
AU - Dauer, Patricia
AU - Sharma, Nikita S.
AU - Gupta, Vineet K.
AU - Durden, Brittany
AU - Hadad, Roey
AU - Banerjee, Santanu
AU - Dudeja, Vikas
AU - Saluja, Ashok
AU - Banerjee, Sulagna
N1 - Funding Information:
The authors would like to acknowledge the Sylvester Comprehensive Cancer Center Flow core for help with flow cytometry; the Mass Spectrometry core for the iTRAQ analysis of the shGRP78 samples and the Oncogenomic core for the transcriptomic analysis of the shGRP78 cells. The authors would also like to thank Dr. Priyamvada Rai and Govindi Jayanika Samaranayake for a critical review of the manuscript and assisting with DNA damage assays. This study was funded by NIH grants R01-CA170946 and R01-CA124723 (to AKS); NIH grant R01-CA184274 (to SB); Katherine and Robert Goodale foundation support (to AKS), Minneamrita Therapeutics LLC (to AKS). The authors would also like to acknowledge the Flow Cytometry Core at the Sylvester Cancer Center, University of Miami for their help with the FACS based assays.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41419-019-1408-5
DO - 10.1038/s41419-019-1408-5
M3 - Article
C2 - 30755605
AN - SCOPUS:85061489558
VL - 10
JO - Cell Death and Disease
JF - Cell Death and Disease
SN - 2041-4889
IS - 2
M1 - 132
ER -