Elsevier

Medical Hypotheses

Volume 74, Issue 6, June 2010, Pages 1038-1043
Medical Hypotheses

Metabolic syndrome is a real disease and premalignant state induced by oncogenic stresses to block malignant transformation

https://doi.org/10.1016/j.mehy.2010.01.001Get rights and content

Summary

Damaged DNA can lead to aneuploidy and/or chromosomal instability, which is believed to be major contributor to tumor progression. Genotoxic and oncogenic stresses-induced DNA damage activate the tumor suppressor pathways initiate 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 and adaptive changes in postmitotic cells. These cellular alterations happen through complex interactions and function to disorder the existing cellular homeostasis. This is a disease state similar to metabolic syndrome occurred by the systemic DDR to inhibit ongoing malignant transformation. Significant metabolic changes occurred by the influence of the major tumor suppressor proteins p53 and FOXO 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.

Introduction

Multicellular organisms contain two fundamentally different cell types: postmitotic cells, which cannot divide, and mitotically competent cells, which can divide. Mitotic tissues have an advantage over postmitotic tissues because they have capable of renewal, repair, and regeneration. The evolution of renewable somatic tissues very likely afforded organisms increased longevity. However, renewable tissues—unlike postmitotic tissues—are susceptible to hyperproliferative disease, the most deadly of which is cancer. This perpetual danger to the gains in longevity was offset by the coevolution of tumor suppressor mechanisms [1].

There is a tight balance between tumor suppression and long-term cell proliferative potential, which is essential for the organisms with renewable tissues [2]. Extensively damaged mitotic cells in complex organisms rely on two different mechanisms, which are cellular senescence and apoptosis [1], [2]. Both represent an irrevocable growth-inhibitory cellular response to oncogenic stress that acts as a potent barrier to the further evolution of any preneoplastic cell [3].

Section snippets

DNA damage response (DDR) in summary

Cellular macromolecules are constantly exposed to both extrinsic and intrinsic damages. Reactive oxygen species (ROS), which are the principal intrinsic insults, are produced during the normal cellular metabolism [3]. When ROS production exceeds the capacity of detoxification can cause oxidative damage to macromolecules including DNA, representing a critical threat to cell function [4].

The evolutionary pressure has led to the development of dynamic systems to cope with this threat [2]. Cell

DDR and p53 related with senescence

The DDR is a fundamental part of senescence and a complex interlaced network compromised of DNA damage repair factors and cell cycle regulators. Perhaps surprisingly for such an important mechanism, after early activation of these proteins, the DDR preferentially converges on a single protein, the tumor suppressor p53 [2].

Over the course of evolution, mammalian cells have acquired an intricate network of protective mechanism to safeguard the genomic integrity. One of the prominent molecules is

ROS, mitochondria and senescence

Nature has integrated redox reactions into a variety of signaling pathways to regulate life processes, by which ROS are recruited as second messengers. Cellular processes in which ROS are involved range from proliferation to senescence and cell death [5]. Interestingly, the concentration of ROS appears important as very high doses of ROS induces cell death, moderate doses induces senescence, while lower doses either are without effect or are actually mitogenic. Thus, ROS would not be mere

Characteristics of cellular senescence related to metabolic syndrome

Cellular senescence is a complex genetic program and a final cell fate decision, which establishes permanent cell cycle arrest in the G1 phase of continuously proliferating cells, in response to stress putting them at risk of malignant transformation [1], [2]. A series of study findings identify senescent cells in several premalignant or benign conditions and show that the senescence program potently prevents tumorigenesis, thereby, placing senescence as an equal partner to apoptosis in tumor

Senescence- and p53-associated metabolic changes

Senescent cells remain viable and metabolically active [4]. DNA damage, whatever the causes, triggers a common, highly conserved stress response which is systemic suppression of insulin/insulin like growth factor 1 (IGF1) hormone axis [4], [9]. This in turn leads to metabolic changes that shift energy usage from growth and proliferation to protective maintenance. Given the central role of DNA damaging free radicals, the activation of DNA repair and anti-oxidant genes under reduced insulin/IGF1

DDR-FOXO-related metabolic changes

Forkhead subgroups of the O class (FOXO) transcription factors contain four members in mammals. The involvement of FOXO factors in cellular processes such as apoptosis, senescence, cell proliferation, and DNA repair is reminiscent of the tumor suppressor protein p53 [28]. FOXO proteins strongly induce the expression of the tumor suppressor genes including p53, p21, and retinoblastoma protein [29].

In response to stress stimuli, FOXO has been found to interact with p53 in complex way. Some

DDR- and senescence-associated changes in somatic cells

Senescence-associated functional alterations in the cells of vasculature play important roles in the formation and progression of cardiovascular disease [8], [34]. Premature vascular senescence is associated with vascular dysfunction, leading to vascular pathologies [34]. Direct analysis of human atherosclerotic plaque has revealed that diseased arterial segments exhibit an accumulation of senescent cells [34]. Cardiovascular risk factors appear to accelerate endothelial cell senescence in a

Hypothesis: DDR-associated senescence and adaptations in postmitotic cells related with the metabolic syndrome

DDR pathway induces self sustaining moderate level of oxidative stress and a metabolic switch that is similar to low glucose and fasting conditions to block the malignant transformation. To maintain sufficient ATP generation under these conditions, cells rely on fatty acid breakdown and oxidative phosphorylation. Shortly, while anabolic function of cell is inhibited, catabolic pathways are supported. Consequently, fundamental mechanisms of the process result in progressive deficits in the

Conclusion

Within the constraints of reproduction, a biological system will always act to reduce oxidative stress and conserve energy. However, acquisition of energy, growth, repair, movement and resistance to infection are all associated with oxidative stress; therefore, redox must have evolved as part of the normal signaling process. Thus life has developed at the edge of chaos and relies on multiple stress-triggered homeostatic mechanisms to keep it there [39].

The antagonistically pleiotropic effects

Conflicts of interest statement

None declared.

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