PMID- 24409315
OWN - NLM
STAT- MEDLINE
DCOM- 20140916
LR  - 20221207
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 1
DP  - 2014
TI  - DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to 
      gemcitabine.
PG  - e84982
LID - 10.1371/journal.pone.0084982 [doi]
LID - e84982
AB  - 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.
FAU - Liu, Fang
AU  - Liu F
AD  - 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.
FAU - Gore, A Jesse
AU  - Gore AJ
AD  - 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.
FAU - Wilson, Julie L
AU  - Wilson JL
AD  - 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.
FAU - Korc, Murray
AU  - Korc M
AD  - 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.
LA  - eng
GR  - P30 CA082709/CA/NCI NIH HHS/United States
GR  - R01 CA075059/CA/NCI NIH HHS/United States
GR  - CA-R37-075059/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140107
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0W860991D6 (Deoxycytidine)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.48 (DUSP1 protein, human)
RN  - EC 3.1.3.48 (Dual Specificity Phosphatase 1)
RN  - Q20Q21Q62J (Cisplatin)
RN  - 0 (Gemcitabine)
SB  - IM
EIN - PLoS One. 2014;9(9):e108710
ECI - PLoS One. 2020 May 21;15(5):e0233098. PMID: 32437453
MH  - Animals
MH  - Antimetabolites, Antineoplastic/*pharmacology/therapeutic use
MH  - Apoptosis/drug effects/genetics
MH  - Cell Line, Tumor
MH  - Cisplatin/pharmacology/therapeutic use
MH  - Deoxycytidine/*analogs & derivatives/pharmacology/therapeutic use
MH  - Disease Models, Animal
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Dual Specificity Phosphatase 1/*genetics/metabolism
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Gene Knockdown Techniques
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Male
MH  - Mice
MH  - Neovascularization, Pathologic/drug therapy/genetics
MH  - Pancreatic Neoplasms/drug therapy/*genetics/metabolism/mortality
MH  - Signal Transduction/drug effects
MH  - Transcription, Genetic
MH  - Xenograft Model Antitumor Assays
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
MH  - Gemcitabine
PMC - PMC3883684
COIS- Competing Interests: Murray Korc is a PLOS ONE Editorial Board member. This does 
      not alter the authors' adherence to all the PLOS ONE policies on sharing data and 
      materials.
EDAT- 2014/01/11 06:00
MHDA- 2014/09/17 06:00
PMCR- 2014/01/07
CRDT- 2014/01/11 06:00
PHST- 2013/10/23 00:00 [received]
PHST- 2013/11/27 00:00 [accepted]
PHST- 2014/01/11 06:00 [entrez]
PHST- 2014/01/11 06:00 [pubmed]
PHST- 2014/09/17 06:00 [medline]
PHST- 2014/01/07 00:00 [pmc-release]
AID - PONE-D-13-43398 [pii]
AID - 10.1371/journal.pone.0084982 [doi]
PST - epublish
SO  - PLoS One. 2014 Jan 7;9(1):e84982. doi: 10.1371/journal.pone.0084982. eCollection 
      2014.