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Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor prognosis. Gemcitabine is the first-line therapy for PDAC, but gemcitabine resistance is a major impediment to achieving satisfactory clinical outcomes. This study investigated whether methylglyoxal (MG), an oncometabolite spontane...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10217245/ https://www.ncbi.nlm.nih.gov/pubmed/37408249 http://dx.doi.org/10.3390/cells12101414 |
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author | Crake, Rebekah Gasmi, Imène Dehaye, Jordan Lardinois, Fanny Peiffer, Raphaël Maloujahmoum, Naïma Agirman, Ferman Koopmansch, Benjamin D’Haene, Nicky Azurmendi Senar, Oier Arsenijevic, Tatjana Lambert, Frédéric Peulen, Olivier Van Laethem, Jean-Luc Bellahcène, Akeila |
author_facet | Crake, Rebekah Gasmi, Imène Dehaye, Jordan Lardinois, Fanny Peiffer, Raphaël Maloujahmoum, Naïma Agirman, Ferman Koopmansch, Benjamin D’Haene, Nicky Azurmendi Senar, Oier Arsenijevic, Tatjana Lambert, Frédéric Peulen, Olivier Van Laethem, Jean-Luc Bellahcène, Akeila |
author_sort | Crake, Rebekah |
collection | PubMed |
description | Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor prognosis. Gemcitabine is the first-line therapy for PDAC, but gemcitabine resistance is a major impediment to achieving satisfactory clinical outcomes. This study investigated whether methylglyoxal (MG), an oncometabolite spontaneously formed as a by-product of glycolysis, notably favors PDAC resistance to gemcitabine. We observed that human PDAC tumors expressing elevated levels of glycolytic enzymes together with high levels of glyoxalase 1 (GLO1), the major MG-detoxifying enzyme, present with a poor prognosis. Next, we showed that glycolysis and subsequent MG stress are triggered in PDAC cells rendered resistant to gemcitabine when compared with parental cells. In fact, acquired resistance, following short and long-term gemcitabine challenges, correlated with the upregulation of GLUT1, LDHA, GLO1, and the accumulation of MG protein adducts. We showed that MG-mediated activation of heat shock response is, at least in part, the molecular mechanism underlying survival in gemcitabine-treated PDAC cells. This novel adverse effect of gemcitabine, i.e., induction of MG stress and HSR activation, is efficiently reversed using potent MG scavengers such as metformin and aminoguanidine. We propose that the MG blockade could be exploited to resensitize resistant PDAC tumors and to improve patient outcomes using gemcitabine therapy. |
format | Online Article Text |
id | pubmed-10217245 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102172452023-05-27 Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response Crake, Rebekah Gasmi, Imène Dehaye, Jordan Lardinois, Fanny Peiffer, Raphaël Maloujahmoum, Naïma Agirman, Ferman Koopmansch, Benjamin D’Haene, Nicky Azurmendi Senar, Oier Arsenijevic, Tatjana Lambert, Frédéric Peulen, Olivier Van Laethem, Jean-Luc Bellahcène, Akeila Cells Article Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor prognosis. Gemcitabine is the first-line therapy for PDAC, but gemcitabine resistance is a major impediment to achieving satisfactory clinical outcomes. This study investigated whether methylglyoxal (MG), an oncometabolite spontaneously formed as a by-product of glycolysis, notably favors PDAC resistance to gemcitabine. We observed that human PDAC tumors expressing elevated levels of glycolytic enzymes together with high levels of glyoxalase 1 (GLO1), the major MG-detoxifying enzyme, present with a poor prognosis. Next, we showed that glycolysis and subsequent MG stress are triggered in PDAC cells rendered resistant to gemcitabine when compared with parental cells. In fact, acquired resistance, following short and long-term gemcitabine challenges, correlated with the upregulation of GLUT1, LDHA, GLO1, and the accumulation of MG protein adducts. We showed that MG-mediated activation of heat shock response is, at least in part, the molecular mechanism underlying survival in gemcitabine-treated PDAC cells. This novel adverse effect of gemcitabine, i.e., induction of MG stress and HSR activation, is efficiently reversed using potent MG scavengers such as metformin and aminoguanidine. We propose that the MG blockade could be exploited to resensitize resistant PDAC tumors and to improve patient outcomes using gemcitabine therapy. MDPI 2023-05-17 /pmc/articles/PMC10217245/ /pubmed/37408249 http://dx.doi.org/10.3390/cells12101414 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Crake, Rebekah Gasmi, Imène Dehaye, Jordan Lardinois, Fanny Peiffer, Raphaël Maloujahmoum, Naïma Agirman, Ferman Koopmansch, Benjamin D’Haene, Nicky Azurmendi Senar, Oier Arsenijevic, Tatjana Lambert, Frédéric Peulen, Olivier Van Laethem, Jean-Luc Bellahcène, Akeila Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response |
title | Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response |
title_full | Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response |
title_fullStr | Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response |
title_full_unstemmed | Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response |
title_short | Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response |
title_sort | resistance to gemcitabine in pancreatic cancer is connected to methylglyoxal stress and heat shock response |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10217245/ https://www.ncbi.nlm.nih.gov/pubmed/37408249 http://dx.doi.org/10.3390/cells12101414 |
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