Diabetes (Type 1 and Type 2) is significantly associated with an increase in all-site cancers, yet how diabetes impacts cancer susceptibility is incompletely understood. Mechanistic hypotheses linking diabetes and cancer have invoked the mitogenic and anti-apoptotic actions of excess insulin and insulin-like growth factor 1 (IGF-1), increased adipokine secretion from fatty tissue, and steroid hormone dysregulation. However, since genomic instability plays a significant role in the initiation and promotion of cancer, we have focused on defining the mechanisms by which diabetes associated metabolic dysfunction contributes to DNA damage and reduced DNA repair. We propose that hyperglycemia-induced DNA damage and inhibition of DNA repair represent important pathological complications of diabetes which exacerbate genomic instability. We will show using tissue culture and diabetic animal models that elevated glucose significantly increases the levels of the DNA adduct N2-(1-carboxyethyl)-2’-deoxyguanosine (CEdG) and it’s RNA analog CEG, and that these adducts are significantly associated with diabetes and diabetic complications. Chronic exposure to elevated glucose also increases DNA strand breaks and inhibits nucleotide excision repair (NER), which is required for removal of CEdG from DNA. Inhibition of NER occurs at the level of gene expression due to metabolism induced destabilization of HIF1α, since many genes of the NER pathway are inducible by this transcription factor. Inhibition also occurs at the level of mTORC1 regulated translation of HIF1α, since DNA damage induces REDD1 (Regulated in Development and DNA Damage responses 1), which dephosphorylates Akt and attenuates mTOR signaling. Since pharmacological agents which stabilize HIF1α or increase translation by mTOR have been described, this raises the possibility of therapeutic intervention to enhanced DNA repair, limit genomic instability, and potentially reduce cancer risk associated with diabetes.

Hyperglycemia induced DNA damage and inhibition of DNA repair: Potential mechanistic link between diabetes and increased cancer risk

2019 Fall National Meeting

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