title: DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a poor prognosis that is characterized by excessive mitogenic pathway activation and marked chemoresistance to a broad spectrum of chemotherapeutic drugs. Dual specificity protein phosphatase 1 (DUSP1) is a key negative regulator of mitogen activated protein kinases (MAPKs). Yet, DUSP1 is overexpressed in pancreatic cancer cells (PCCs) in PDAC where it paradoxically enhances colony formation in soft agar and promotes in vivo tumorigenicity. However, it is not known whether DUSP1 overexpression contributes to PDAC chemoresistance. Using BxPC3 and COLO-357 human PCCs, we show that gemcitabine activates c-JUN N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38 MAPK), key kinases in two major stress-activated signaling pathways. Gemcitabine-induced JNK and p38 MAPK activation mediates increased apoptosis, but also transcriptionally upregulates DUSP1, as evidenced by increased DUSP1 mRNA levels and RNA polymerase II loading at DUSP1 gene body. Conversely, shRNA-mediated inhibition of DUSP1 enhances JNK and p38 MAPK activation and gemcitabine chemosensitivity. Using doxycycline-inducible knockdown of DUSP1 in established orthotopic pancreatic tumors, we found that combining gemcitabine with DUSP1 inhibition improves animal survival, attenuates angiogenesis, and enhances apoptotic cell death, as compared with gemcitabine alone. Taken together, these results suggest that gemcitabine-mediated upregulation of DUSP1 contributes to a negative feedback loop that attenuates its beneficial actions on stress pathways and apoptosis, raising the possibility that targeting DUSP1 in PDAC may have the advantage of enhancing gemcitabine chemosensitivity while suppressing angiogenesis.
authors.affiliation: Departments of Medicine, Biochemistry and Molecular Biology, Indiana University School of Medicine, The Melvin and Bren Simon Cancer Center and the Center for Pancreatic Cancer Research, Indianapolis, Indiana, United States of America.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Departments of Medicine, Biochemistry and Molecular Biology, Indiana University School of Medicine, The Melvin and Bren Simon Cancer Center and the Center for Pancreatic Cancer Research, Indianapolis, Indiana, United States of America.
authors.forename: A Jesse
authors.initials: AJ
authors.lastname: Gore
authors.affiliation: Departments of Medicine, Biochemistry and Molecular Biology, Indiana University School of Medicine, The Melvin and Bren Simon Cancer Center and the Center for Pancreatic Cancer Research, Indianapolis, Indiana, United States of America.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Wilson
authors.affiliation: Departments of Medicine, Biochemistry and Molecular Biology, Indiana University School of Medicine, The Melvin and Bren Simon Cancer Center and the Center for Pancreatic Cancer Research, Indianapolis, Indiana, United States of America.
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D002945:Cisplatin; D000093542:Gemcitabine