Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells.

Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells.

<h4>Background</h4>RRM1 is functionally associated with DNA replication and DNA damage repair. However, the biological activity of RRM1 in pancreatic cancer remains undetermined.<h4>Methods</h4>To determine relationships between RRM1 expression and the prognosis of pancreatic...

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Autores principales: Tomotaka Kato, Hiroaki Ono, Mikiya Fujii, Keiichi Akahoshi, Toshiro Ogura, Kosuke Ogawa, Daisuke Ban, Atsushi Kudo, Shinji Tanaka, Minoru Tanabe
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2021
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Medicine
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Science
Q
Acceso en línea:https://doaj.org/article/19daacf79f83433994bc25b4b85bc1e3
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spelling oai:doaj.org-article:19daacf79f83433994bc25b4b85bc1e32021-12-02T20:10:50ZCytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells.1932-620310.1371/journal.pone.0252917https://doaj.org/article/19daacf79f83433994bc25b4b85bc1e32021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0252917https://doaj.org/toc/1932-6203<h4>Background</h4>RRM1 is functionally associated with DNA replication and DNA damage repair. However, the biological activity of RRM1 in pancreatic cancer remains undetermined.<h4>Methods</h4>To determine relationships between RRM1 expression and the prognosis of pancreatic cancer, and to explore RRM1 function in cancer biology, we investigated RRM1 expression levels in 121 pancreatic cancer patients by immunohistochemical staining and performed in vitro experiments to analyze the functional consequences of RRM1 expression.<h4>Results</h4>Patients with high RRM1 expression had significantly poorer clinical outcomes (overall survival; p = 0.006, disease-free survival; p = 0.0491). In particular, high RRM1 expression was also associated with poorer overall survival on adjuvant chemotherapy (p = 0.008). We found that RRM1 expression was increased 24 hours after exposure to gemcitabine and could be suppressed by histone acetyltransferase inhibition. RRM1 activation in response to gemcitabine exposure was induced mainly in the cytoplasm and cytoplasmic RRM1 activation was related to cancer cell viability. In contrast, cancer cells lacking cytoplasmic RRM1 activation were confirmed to show severe DNA damage. RRM1 inhibition with specific siRNA or hydroxyurea enhanced the cytotoxic effects of gemcitabine for pancreatic cancer cells.<h4>Conclusions</h4>Cytoplasmic RRM1 activation is involved in biological processes related to drug resistance in response to gemcitabine exposure and could be a potential target for pancreatic cancer treatment.Tomotaka KatoHiroaki OnoMikiya FujiiKeiichi AkahoshiToshiro OguraKosuke OgawaDaisuke BanAtsushi KudoShinji TanakaMinoru TanabePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0252917 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Tomotaka Kato
Hiroaki Ono
Mikiya Fujii
Keiichi Akahoshi
Toshiro Ogura
Kosuke Ogawa
Daisuke Ban
Atsushi Kudo
Shinji Tanaka
Minoru Tanabe
Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells.
description <h4>Background</h4>RRM1 is functionally associated with DNA replication and DNA damage repair. However, the biological activity of RRM1 in pancreatic cancer remains undetermined.<h4>Methods</h4>To determine relationships between RRM1 expression and the prognosis of pancreatic cancer, and to explore RRM1 function in cancer biology, we investigated RRM1 expression levels in 121 pancreatic cancer patients by immunohistochemical staining and performed in vitro experiments to analyze the functional consequences of RRM1 expression.<h4>Results</h4>Patients with high RRM1 expression had significantly poorer clinical outcomes (overall survival; p = 0.006, disease-free survival; p = 0.0491). In particular, high RRM1 expression was also associated with poorer overall survival on adjuvant chemotherapy (p = 0.008). We found that RRM1 expression was increased 24 hours after exposure to gemcitabine and could be suppressed by histone acetyltransferase inhibition. RRM1 activation in response to gemcitabine exposure was induced mainly in the cytoplasm and cytoplasmic RRM1 activation was related to cancer cell viability. In contrast, cancer cells lacking cytoplasmic RRM1 activation were confirmed to show severe DNA damage. RRM1 inhibition with specific siRNA or hydroxyurea enhanced the cytotoxic effects of gemcitabine for pancreatic cancer cells.<h4>Conclusions</h4>Cytoplasmic RRM1 activation is involved in biological processes related to drug resistance in response to gemcitabine exposure and could be a potential target for pancreatic cancer treatment.
format article
author Tomotaka Kato
Hiroaki Ono
Mikiya Fujii
Keiichi Akahoshi
Toshiro Ogura
Kosuke Ogawa
Daisuke Ban
Atsushi Kudo
Shinji Tanaka
Minoru Tanabe
author_facet Tomotaka Kato
Hiroaki Ono
Mikiya Fujii
Keiichi Akahoshi
Toshiro Ogura
Kosuke Ogawa
Daisuke Ban
Atsushi Kudo
Shinji Tanaka
Minoru Tanabe
author_sort Tomotaka Kato
title Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells.
title_short Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells.
title_full Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells.
title_fullStr Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells.
title_full_unstemmed Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells.
title_sort cytoplasmic rrm1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells.
publisher Public Library of Science (PLoS)
publishDate 2021
url https://doaj.org/article/19daacf79f83433994bc25b4b85bc1e3
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AT hiroakiono cytoplasmicrrm1activationasanacuteresponsetogemcitabinetreatmentisinvolvedindrugresistanceofpancreaticcancercells
AT mikiyafujii cytoplasmicrrm1activationasanacuteresponsetogemcitabinetreatmentisinvolvedindrugresistanceofpancreaticcancercells
AT keiichiakahoshi cytoplasmicrrm1activationasanacuteresponsetogemcitabinetreatmentisinvolvedindrugresistanceofpancreaticcancercells
AT toshiroogura cytoplasmicrrm1activationasanacuteresponsetogemcitabinetreatmentisinvolvedindrugresistanceofpancreaticcancercells
AT kosukeogawa cytoplasmicrrm1activationasanacuteresponsetogemcitabinetreatmentisinvolvedindrugresistanceofpancreaticcancercells
AT daisukeban cytoplasmicrrm1activationasanacuteresponsetogemcitabinetreatmentisinvolvedindrugresistanceofpancreaticcancercells
AT atsushikudo cytoplasmicrrm1activationasanacuteresponsetogemcitabinetreatmentisinvolvedindrugresistanceofpancreaticcancercells
AT shinjitanaka cytoplasmicrrm1activationasanacuteresponsetogemcitabinetreatmentisinvolvedindrugresistanceofpancreaticcancercells
AT minorutanabe cytoplasmicrrm1activationasanacuteresponsetogemcitabinetreatmentisinvolvedindrugresistanceofpancreaticcancercells
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