RICERCA ITALIANA     

REDOX MECHANISMS UNDERLYING CELL SIGNALING INVOLVED IN THE GENESIS OF OXIDATIVE STRESS-RELATED DISEASES

Università degli Studi di Roma "Tor Vergata"

Abstract

Cells communicate each other and respond to extracellular stimuli through biological mechanisms, which transform the signal in chemical modifications; this process is named cellular signaling or signal transduction and represents a common property of viable cells. Recently, beside the well known phosphorylative signaling cascade regulating diverse functions and responses of the cell, another modality of signal transduction with redox features, mediated by the reactive oxygen (ROS) and nitrogen (RNS) species, has been discovered.
The ROS-induced cellular responses include the expression and the synthesis of cytokines, growth factors and hormones, with a consequent influence on cell cycle, differentiation, resistance, senescence and apoptotic cell death. Most likely, on the basis of these potential responses there are discrete modifications of cellular redox state, which lead to the onset of precise molecular signals and their transduction into the nucleus.
The Units involved in this project are attracted, from several years, in diverse aspects related to alterations of the redox status, in experimental models of pathologies of great impact for the human health such as cancer, atherosclerosis, and neurodegeneration or for physiological conditions such as ageing and cellular senescence. Therefore, the aim of the Units in the present project is at contributing to the elucidation of the main mechanisms through which ROS, as well as molecules derived from their >>>

Principal Investigator

Maria Rosa Ciriolo Università degli Studi di ROMA "Tor Vergata"

Research Objectives

Our research has the principal goal to identify the molecular mechanisms underlying the redox signal transduction pathways which determine the different cellular response in dependence on the nature/intensity of the redox stimuli applied in cellular models of pathological states such as cancer, neurodegeneration senescence and atherosclerosis. Below are reported the aims of each task included in the present project.

1. Cancer
Several are the processes at the basis of transformed phenotype but they are basically characterised by the concomitant deregulation of death and proliferative processes. The involvement of oxidative stress in tumorigenesis seems to have a double aspect: from one hand, it is involved in the onset of mutations responsible for the neoplastic transformation with the following uncontrolled induction of proliferation and the occurrence of resistance; from the other hand, it could represent a tool to selectively induce cell death during tumour progression. In this context, the aims of our research project will be subdivided as following:

A) To clarify the role of redox signalling, from the upstream MAP kinase (JNK, p38MAPK and ERK1/2) to the downstream transcription factors (Nrf-2, NF-kappaB, AP1), in the modulation of apoptosis induced by diverse oxidative stimuli, in order to understand the causes of different susceptibility (resistance/death) to oxidative stress in transformed cells of different origin.

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First Results

The expected results of this research program are reported subdivided in sections that identifying human conditions or pathologies associated with oxidative stress, following the scheme delineated in the status of art of the project.


1. CANCER

A. Role of the intracellular thiol state and of the activation of the redox-sensitive members of MAP kinase family and transcription factors as molecular switches determining the susceptibility to oxidative stress in transformed cells of different origin.
Results previously obtained and preliminary data of Ciriolo’s Unit propose the existence of a different histotype-dependent susceptibility towards oxidative stress. This feature accounts for the diverse equipment of antioxidants and for the selective activation of phosphorylative cascade mediated by specific classes of MAPK. On the basis of these data and according to what has been proposed, Ciriolo’s Unit expectations are:
1) The clarification of the molecular mechanisms underlying the histotype-dependent response to different oxidative stresses.
2) The characterization of the redox equipment and the degree of sensitivity of diverse tumor histotypes towards diverse pro-oxidant agents.
The results obtained will be useful to select classes of chemothepeutics with specific pro-oxidant action on tumor cell lines with different redox features. Moreover, they could allow hypothesizing a screening for proteins and >>>

Timescale

24 months

National and international background

Several data demonstrated a key role for oxidative stress in mediating aging, tumorigenesis as well as the etiology of numerous vascular and neurodegenerative diseases . Reactive oxygen species (ROS) are the products of partial reduction of oxygen thus representing the physiological by-products of oxidative metabolism. Among the sources of ROS, NAD(P)H oxidases and the mitochondrial electrons transport chain are the major endogenous producers; alternatively, chemical and physical stresses, such as UV radiations, pollutants, drugs and xenobiotics (e.g. anthracyclins) can generate ROS at high concentrations.
Among ROS-mediated oxidative modifications, those on lipids represent the former to be studied and identified. Recent evidence shows that cholesterol could also represent a target for ROS-mediated oxidative insult, giving rise to the formation of oxysterols. Among the lipid oxidation products of particular interest in age-related pathophysiology are oxysterols, being often quantitatively increased in the blood and possibly in the arteries of the aged individual. Most likely, oxysterols provide a primary contribution to the whole atherogenetic process not only through the activation of pro-inflammatory and pro-fibrogenic pathways, but also by sustaining the overexpression of apoptotic death of vascular cells, especially in the advanced stages of the atherogenic process. Over the last decade, reliable in vitro studies characterized the potential pro-apoptotic effect >>>