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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-05-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/10/1414 |
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| author | Rebekah Crake Imène Gasmi Jordan Dehaye Fanny Lardinois Raphaël Peiffer Naïma Maloujahmoum Ferman Agirman Benjamin Koopmansch Nicky D’Haene Oier Azurmendi Senar Tatjana Arsenijevic Frédéric Lambert Olivier Peulen Jean-Luc Van Laethem Akeila Bellahcène |
| author_facet | Rebekah Crake Imène Gasmi Jordan Dehaye Fanny Lardinois Raphaël Peiffer Naïma Maloujahmoum Ferman Agirman Benjamin Koopmansch Nicky D’Haene Oier Azurmendi Senar Tatjana Arsenijevic Frédéric Lambert Olivier Peulen Jean-Luc Van Laethem Akeila Bellahcène |
| author_sort | Rebekah Crake |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T03:50:49Z |
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| id | doaj.art-783f0eb541c3480e8e03caf7a479f4db |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T03:50:49Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-783f0eb541c3480e8e03caf7a479f4db2023-11-18T00:53:18ZengMDPI AGCells2073-44092023-05-011210141410.3390/cells12101414Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock ResponseRebekah Crake0Imène Gasmi1Jordan Dehaye2Fanny Lardinois3Raphaël Peiffer4Naïma Maloujahmoum5Ferman Agirman6Benjamin Koopmansch7Nicky D’Haene8Oier Azurmendi Senar9Tatjana Arsenijevic10Frédéric Lambert11Olivier Peulen12Jean-Luc Van Laethem13Akeila Bellahcène14Metastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, 4020 Liège, BelgiumMetastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, 4020 Liège, BelgiumMetastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, 4020 Liège, BelgiumMetastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, 4020 Liège, BelgiumMetastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, 4020 Liège, BelgiumMetastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, 4020 Liège, BelgiumMetastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, 4020 Liège, BelgiumDepartment of Human Genetics, Liège University Hospital, 4020 Liège, BelgiumDepartment of Pathology, Hôpital Universitaire de Bruxelles Bordet Erasme l Hospital, Université Libre de Bruxelles, 1000 Brussels, BelgiumLaboratory of Experimental Gastroenterology, Medical Faculty, Université Libre de Bruxelles, 1000 Brussels, BelgiumLaboratory of Experimental Gastroenterology, Medical Faculty, Université Libre de Bruxelles, 1000 Brussels, BelgiumDepartment of Human Genetics, Liège University Hospital, 4020 Liège, BelgiumMetastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, 4020 Liège, BelgiumLaboratory of Experimental Gastroenterology, Medical Faculty, Université Libre de Bruxelles, 1000 Brussels, BelgiumMetastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, 4020 Liège, BelgiumPancreatic 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.https://www.mdpi.com/2073-4409/12/10/1414oncometabolitemethylglyoxalglycolysistherapy resistancegemcitabinemetformin |
| spellingShingle | Rebekah Crake Imène Gasmi Jordan Dehaye Fanny Lardinois Raphaël Peiffer Naïma Maloujahmoum Ferman Agirman Benjamin Koopmansch Nicky D’Haene Oier Azurmendi Senar Tatjana Arsenijevic Frédéric Lambert Olivier Peulen Jean-Luc Van Laethem Akeila Bellahcène Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response Cells oncometabolite methylglyoxal glycolysis therapy resistance gemcitabine metformin |
| 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 | oncometabolite methylglyoxal glycolysis therapy resistance gemcitabine metformin |
| url | https://www.mdpi.com/2073-4409/12/10/1414 |
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