Abstract
Impaired signaling pathways as a result of the increased oxidative stress and general metabolic dysregulation seen in metabolic syndrome may contribute to the increased cancer risk seen in otherwise healthy patients; and subsequent development of progressive cancer characterized by metastatic process. Oxidative stress leading to insulin resistance is a major component of the metabolic syndrome. Dysregulation of the Renin-Angiotensin-Aldosterone (RAAS) axis is known to be one of the major risk factors for metabolic syndrome; and recently has been shown to play a significant contributory role in the development of oxidative stress; leading up to insulin resistance; in the metabolic syndrome by several different groups. In recent years; angiotensin and aldosterone have emerged as important contributory pathogenic factors for the development of metabolic syndrome; primarily through their ability to cause cellular oxidative stress. Angiotensin (Ang II) can also induce oxidative stress through activation of NADPH oxidase. Recently; metabolic syndrome has been associated with increased risk for a variety of cancers. Since oxidative stress is a critical component of the metabolic syndrome; it stands to reason that Ang II excess would increase oxidative stress and contribute further to increased cancer risk in terms of epigenetic dysregulation in stressed cells. Thus the purpose of this study is to check the effect of the RAAS axis on cancer development and characterize the intracellular signaling pathways involved. Specifically; the correlation of cancer incidence and spread to Ang II treatment and levels of oxidative stress will allow us to analyze the role of the vital contributory components of the metabolic syndrome in cancer.
Highlights
Background and significanceMetabolic syndrome is a recognized clinical entity which can persist for years and precedes the development of overt clinical conditions [1]
It is expected that oxidative stress will be significantly elevated due to Ang II treatment in conditions of metabolic syndrome and contribute to the development and progression of epigenetic cellular dysregulation, which precedes cancer
In addition to generating significant information pertaining to the signaling networks involved in the link between Ang II and cancer in response to oxidative stress, the study will provide additional translational and research value for cancer progression and risk in the context of the metabolic syndrome and insulin resistance, as it will serve to identify the regulatory and/or signaling pathways involved in Renin-Angiotensin-Aldosterone Axis (RAAS)-mediated impaired metabolic signaling pathways
Summary
Background and significanceMetabolic syndrome is a recognized clinical entity which can persist for years and precedes the development of overt clinical conditions [1]. Ang II, which is one of the main effector molecules of the RAAS axis, can bind the NADPH oxidase receptor directly and can cause oxidative stress [7,8] It can cause increased intracellular oxidative stress through activation of its own receptor AT1, which leads to stimulation of the stress-responsive kinases and increased production of intracellular ROS [9]. All of this can stimulate activation of pro-inflammatory pathways and cell necrosis, contributing eventually to epigenetic dysregulation of cellular homeostasis and cancer development. Since both oxidative stress and RAAS axis dysregulation can contribute to cellular injury [5], it would be interesting to elucidate the role of these components in the development of cancer in the context of the metabolic syndrome
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