DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.

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 mit...

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Autores principales:	Fang Liu, A Jesse Gore, Julie L Wilson, Murray Korc
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2f551db8aca741ffb4bf3fe21fc5c62e
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spelling	oai:doaj.org-article:2f551db8aca741ffb4bf3fe21fc5c62e2021-11-18T08:38:44ZDUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.1932-620310.1371/journal.pone.0084982https://doaj.org/article/2f551db8aca741ffb4bf3fe21fc5c62e2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24409315/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Pancreatic 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.Fang LiuA Jesse GoreJulie L WilsonMurray KorcPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 1, p e84982 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Fang Liu A Jesse Gore Julie L Wilson Murray Korc DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.
description	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.
format	article
author	Fang Liu A Jesse Gore Julie L Wilson Murray Korc
author_facet	Fang Liu A Jesse Gore Julie L Wilson Murray Korc
author_sort	Fang Liu
title	DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.
title_short	DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.
title_full	DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.
title_fullStr	DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.
title_full_unstemmed	DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.
title_sort	dusp1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/2f551db8aca741ffb4bf3fe21fc5c62e
work_keys_str_mv	AT fangliu dusp1isanoveltargetforenhancingpancreaticcancercellsensitivitytogemcitabine AT ajessegore dusp1isanoveltargetforenhancingpancreaticcancercellsensitivitytogemcitabine AT julielwilson dusp1isanoveltargetforenhancingpancreaticcancercellsensitivitytogemcitabine AT murraykorc dusp1isanoveltargetforenhancingpancreaticcancercellsensitivitytogemcitabine
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DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.

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