Systemic DNA Damage Response and Metabolic Syndrome as a Premalignant State

Damaged DNA can lead to aneuploidy and/or chromosomal instability, which is believed to be major contributor to tumor progression. DNA damage in response to genotoxic and oncogenic stresses activate the tumor suppressor pathways initiating DNA damage response (DDR). One of the cellular fates in response to DDR is permanent growth arrest in mitotically active cells, including stem cells, leading to senescence. On the other hand, DDR reasons in adaptive changes in postmitotic cells. These cellular alterations happen through complex interactions and function to disrupt the existing cellular homeostasis. Significant metabolic changes occurred by the influence of the major tumor suppressor protein p53 and other related factors such as FOXO, AMPK, PARP, NF-κB and PGC-1 are discussed in the article. After a strong correlation established between the systemic DNA damage response to inhibit ongoing malignant transformation and metabolic syndrome characteristics, logical extrapolations for type 2 diabetes, cardiovascular disease, and aging are carried out. Finally, therapeutic evaluations are performed in the light of the novel pathophysiological data implying that “metabolic syndrome” is a real disease.