Diabetes promotes invasive pancreatic cancer by increasing systemic and tumour carbonyl stress in Kras
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Cell Cycle Proteins
/ metabolism
Diabetes Complications
/ etiology
Diabetes Mellitus, Experimental
/ complications
Glycation End Products, Advanced
/ metabolism
Mice
Mice, Transgenic
Mutation
Oxidative Stress
Pancreatic Neoplasms
/ etiology
Proto-Oncogene Proteins p21(ras)
/ genetics
Reactive Oxygen Species
/ metabolism
YAP-Signaling Proteins
Advanced glycation end-products
Carnosine derivatives
Epidermal growth factor receptor
Extracellular signal-regulated kinases 1/2
Hyperglycaemia
Large tumour suppressor kinase 1
Methylglyoxal
Pancreatic ductal adenocarcinoma
Reactive carbonyl species
Yes-associated protein
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
10 Aug 2020
10 Aug 2020
Historique:
received:
30
03
2020
accepted:
04
08
2020
entrez:
12
8
2020
pubmed:
12
8
2020
medline:
28
4
2021
Statut:
epublish
Résumé
Type 1 and 2 diabetes confer an increased risk of pancreatic cancer (PaC) of similar magnitude, suggesting a common mechanism. The recent finding that PaC incidence increases linearly with increasing fasting glucose levels supports a central role for hyperglycaemia, which is known to cause carbonyl stress and advanced glycation end-product (AGE) accumulation through increased glycolytic activity and non-enzymatic reactions. This study investigated the impact of hyperglycaemia on invasive tumour development and the underlying mechanisms involved. Pdx1-Cre;LSL-Kras Cumulative incidence of invasive PaC at 22 weeks of age was 75% in untreated diabetic vs 25% in FL-926-16-gtreated diabetic and 8.3% in non-diabetic mice. FL-926-16 treatment suppressed systemic and pancreatic carbonyl stress, extracellular signal-regulated kinases (ERK) 1/2 activation, and nuclear translocation of Yes-associated protein (YAP) in pancreas. In vitro, RCS scavenging and AGE elimination completely inhibited cell proliferation stimulated by high glucose, and YAP proved essential in mediating the effects of both glucose-derived RCS and their protein adducts AGEs. However, RCS and AGEs induced YAP activity through distinct pathways, causing reduction of Large Tumour Suppressor Kinase 1 and activation of the Epidermal Growth Factor Receptor/ERK signalling pathway, respectively. An RCS scavenger and AGE inhibitor prevented the accelerating effect of diabetes on PainINs progression to invasive PaC, showing that hyperglycaemia promotes PaC mainly through increased carbonyl stress. In vitro experiments demonstrated that both circulating RCS/AGEs and tumour cell-derived carbonyl stress generated by excess glucose metabolism induce proliferation by YAP activation, hence providing a molecular mechanism underlying the link between diabetes and PaC (and cancer in general).
Sections du résumé
BACKGROUND
BACKGROUND
Type 1 and 2 diabetes confer an increased risk of pancreatic cancer (PaC) of similar magnitude, suggesting a common mechanism. The recent finding that PaC incidence increases linearly with increasing fasting glucose levels supports a central role for hyperglycaemia, which is known to cause carbonyl stress and advanced glycation end-product (AGE) accumulation through increased glycolytic activity and non-enzymatic reactions. This study investigated the impact of hyperglycaemia on invasive tumour development and the underlying mechanisms involved.
METHODS
METHODS
Pdx1-Cre;LSL-Kras
RESULTS
RESULTS
Cumulative incidence of invasive PaC at 22 weeks of age was 75% in untreated diabetic vs 25% in FL-926-16-gtreated diabetic and 8.3% in non-diabetic mice. FL-926-16 treatment suppressed systemic and pancreatic carbonyl stress, extracellular signal-regulated kinases (ERK) 1/2 activation, and nuclear translocation of Yes-associated protein (YAP) in pancreas. In vitro, RCS scavenging and AGE elimination completely inhibited cell proliferation stimulated by high glucose, and YAP proved essential in mediating the effects of both glucose-derived RCS and their protein adducts AGEs. However, RCS and AGEs induced YAP activity through distinct pathways, causing reduction of Large Tumour Suppressor Kinase 1 and activation of the Epidermal Growth Factor Receptor/ERK signalling pathway, respectively.
CONCLUSIONS
CONCLUSIONS
An RCS scavenger and AGE inhibitor prevented the accelerating effect of diabetes on PainINs progression to invasive PaC, showing that hyperglycaemia promotes PaC mainly through increased carbonyl stress. In vitro experiments demonstrated that both circulating RCS/AGEs and tumour cell-derived carbonyl stress generated by excess glucose metabolism induce proliferation by YAP activation, hence providing a molecular mechanism underlying the link between diabetes and PaC (and cancer in general).
Identifiants
pubmed: 32778157
doi: 10.1186/s13046-020-01665-0
pii: 10.1186/s13046-020-01665-0
pmc: PMC7418209
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Cell Cycle Proteins
0
Glycation End Products, Advanced
0
KRAS protein, human
0
Reactive Oxygen Species
0
YAP-Signaling Proteins
0
Yap1 protein, mouse
0
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
152Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG - 17640
Organisme : Sapienza Università di Roma
ID : N/A
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