Format

Send to

Choose Destination
J Mol Endocrinol. 2013 Dec 19;52(1):R51-66. doi: 10.1530/JME-13-0152. Print 2014 Feb.

A new link between diabetes and cancer: enhanced WNT/β-catenin signaling by high glucose.

Author information

1
Departamento de Fisiología y Bioquímica, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, 28922 Alcorcon, Madrid, Spain Unidad Funcional de Investigación en Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain.

Abstract

Extensive epidemiological studies suggest that the diabetic population is at higher risk of site-specific cancers. The diabetes-cancer link has been hypothesized to rely on various hormonal (insulin, IGF1, adipokines), immunological (inflammation), or metabolic (hyperglycemia) characteristics of the disease and even on certain treatments. Inflammation may have an important but incompletely understood role. As a growth factor, insulin directly, or indirectly through IGF1, has been considered the major link between diabetes and cancer, while high glucose has been considered as a subordinate cause. Here we discuss the evidence that supports a role for insulin/IGF1 in general in cancer, and the mechanism by which hyperglycemia may enhance the appearance, growth and survival of diabetes-associated cancers. High glucose triggers several direct and indirect mechanisms that cooperate to promote cancer cell proliferation, migration, invasion and immunological escape. In particular, high glucose enhancement of WNT/β-catenin signaling in cancer cells promotes proliferation, survival and senescence bypass, and represents a previously unrecognized direct mechanism linking diabetes-associated hyperglycemia to cancer. Increased glucose uptake is a hallmark of tumor cells and may ensure enhanced WNT signaling for continuous proliferation. Mechanistically, high glucose unbalances acetylation through increased p300 acetyl transferase and decreased sirtuin 1 deacetylase activity, leading to β-catenin acetylation at lysine K354, a requirement for nuclear accumulation and transcriptional activation of WNT-target genes. The impact of high glucose on β-catenin illustrates the remodeling of cancer-associated signaling pathways by metabolites. Metabolic remodeling of cancer-associated signaling will receive much research attention in the coming years. Future epidemiological studies may be guided and complemented by the identification of these metabolic interplays. Together, these studies should lead to the development of new preventive strategies for diabetes-associated cancers.

KEYWORDS:

WNT; cancer; diabetes; glucose-dependent insulinotropic peptide; incretin; insulin; signaling; transcription; β-catenin

PMID:
24049067
DOI:
10.1530/JME-13-0152
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Sheridan PubFactory
Loading ...
Support Center