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Diabetes and Pancreatic Cancer—A Dangerous Liaison Relying on Carbonyl Stress

1
Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy
2
Department of Neurosciences, Rehabilitation, Ophtalmology, Genetic and Maternal Infantile Sciences (DINOGMI), Department of Excellence of MIUR, University of Genoa Medical School, 16132 Genoa, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2021, 13(2), 313; https://doi.org/10.3390/cancers13020313
Received: 14 December 2020 / Revised: 9 January 2021 / Accepted: 14 January 2021 / Published: 16 January 2021
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
Diabetic people have an increased risk of developing several types of cancers, particularly pancreatic cancer. The higher availability of glucose and/or lipids that characterizes diabetes and obesity is responsible for the increased production of highly reactive carbonyl compounds, a condition referred to as “carbonyl stress”. Also known as glycotoxins and lipotoxins, these compounds react quickly and damage various molecules in cells forming final products termed AGEs (advanced glycation end-products). AGEs were shown to markedly accelerate tumor development in an experimental model of pancreatic cancer and AGE inhibition prevented the tumor-promoting effect of diabetes. In humans, carbonyl stress has been associated with the risk of pancreatic cancer and recognized as a possible contributor to other cancers, including breast and colorectal cancer. These findings suggest that carbonyl stress is involved in cancer development and growth and may be the mechanistic link between diabetes and pancreatic cancer, thus representing a potential drug target.
Both type 2 (T2DM) and type 1 (T1DM) diabetes mellitus confer an increased risk of pancreatic cancer in humans. The magnitude and temporal trajectory of the risk conferred by the two forms of diabetes are similar, suggesting a common mechanism. Carbonyl stress is a hallmark of hyperglycemia and dyslipidemia, which accompanies T2DM, prediabetes, and obesity. Accumulating evidence demonstrates that diabetes promotes pancreatic ductal adenocarcinoma (PDAC) in experimental models of T2DM, a finding recently confirmed in a T1DM model. The carbonyl stress markers advanced glycation end-products (AGEs), the levels of which are increased in diabetes, were shown to markedly accelerate tumor development in a mouse model of Kras-driven PDAC. Consistently, inhibition of AGE formation by trapping their carbonyl precursors (i.e., reactive carbonyl species, RCS) prevented the PDAC-promoting effect of diabetes. Considering the growing attention on carbonyl stress in the onset and progression of several cancers, including breast, lung and colorectal cancer, this review discusses the mechanisms by which glucose and lipid imbalances induce a status of carbonyl stress, the oncogenic pathways activated by AGEs and their precursors RCS, and the potential use of carbonyl-scavenging agents and AGE inhibitors in PDAC prevention and treatment, particularly in high-risk diabetic individuals. View Full-Text
Keywords: pancreatic ductal adenocarcinoma; hyperglycemia; obesity; reactive carbonyl species; methylglyoxal; receptor for advanced glycation end-products; carnosine derivatives; yes-associated protein; epithelial growth factor receptor pancreatic ductal adenocarcinoma; hyperglycemia; obesity; reactive carbonyl species; methylglyoxal; receptor for advanced glycation end-products; carnosine derivatives; yes-associated protein; epithelial growth factor receptor
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MDPI and ACS Style

Menini, S.; Iacobini, C.; Vitale, M.; Pesce, C.; Pugliese, G. Diabetes and Pancreatic Cancer—A Dangerous Liaison Relying on Carbonyl Stress. Cancers 2021, 13, 313. https://doi.org/10.3390/cancers13020313

AMA Style

Menini S, Iacobini C, Vitale M, Pesce C, Pugliese G. Diabetes and Pancreatic Cancer—A Dangerous Liaison Relying on Carbonyl Stress. Cancers. 2021; 13(2):313. https://doi.org/10.3390/cancers13020313

Chicago/Turabian Style

Menini, Stefano; Iacobini, Carla; Vitale, Martina; Pesce, Carlo; Pugliese, Giuseppe. 2021. "Diabetes and Pancreatic Cancer—A Dangerous Liaison Relying on Carbonyl Stress" Cancers 13, no. 2: 313. https://doi.org/10.3390/cancers13020313

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