Article (Scientific journals)
Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response
Crake, Rebekah; Gasmi, Imène; Dehaye, Jordan et al.
2023In Cells, 12 (10), p. 1414
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Keywords :
Pancreatic Cancer; Gemcitabine; Metabolism; Glycolysis; Oncometabolite; Methylglyoxal; Heat shock response; Resistance
Abstract :
[en] 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.
Disciplines :
Oncology
Author, co-author :
Crake, Rebekah  ;  Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Gasmi, Imène;  Metastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, 4020 Liège, Belgium
Dehaye, Jordan;  Metastasis Research Laboratory, GIGA-Cancer, GIGA Institute, University of Liège, 4020 Liège, Belgium
Lardinois, Fanny  ;  Université de Liège - ULiège > GIGA
Peiffer, Raphaël  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Maloujahmoum, Naïma ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Agirman, Ferman ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
KOOPMANSCH, Benjamin  ;  Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
D’Haene, Nicky;  Department of Pathology, Hôpital Universitaire de Bruxelles Bordet Erasme l Hospital, Université Libre de Bruxelles, 1000 Brussels, Belgium
Azurmendi Senar, Oier;  Laboratory of Experimental Gastroenterology, Medical Faculty, Université Libre de Bruxelles, 1000 Brussels, Belgium
Arsenijevic, Tatjana;  Laboratory of Experimental Gastroenterology, Medical Faculty, Université Libre de Bruxelles, 1000 Brussels, Belgium ; Department of Gastroenterology, Hepatology and Digestive Oncology, Hôpital Universitaire de Bruxelles Bordet Erasme Hospital, Université Libre de Bruxelles, 1000 Brussels, Belgium
Lambert, Frédéric  ;  Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
Peulen, Olivier  ;  Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory
Van Laethem, Jean-Luc;  Laboratory of Experimental Gastroenterology, Medical Faculty, Université Libre de Bruxelles, 1000 Brussels, Belgium ; Department of Gastroenterology, Hepatology and Digestive Oncology, Hôpital Universitaire de Bruxelles Bordet Erasme Hospital, Université Libre de Bruxelles, 1000 Brussels, Belgium
Bellahcene, Akeila  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
More authors (5 more) Less
Language :
English
Title :
Resistance to Gemcitabine in Pancreatic Cancer Is Connected to Methylglyoxal Stress and Heat Shock Response
Publication date :
17 May 2023
Journal title :
Cells
eISSN :
2073-4409
Publisher :
MDPI AG
Volume :
12
Issue :
10
Pages :
1414
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fund for Scientific Research [BE]
ULiège - University of Liège [BE]
Fondation Léon Fredericq [BE]
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