PSYCHOLOGICAL STRESS PROMOTES IRRADIATION-INDUCED TUMORIGENESIS THROUGH ATTENUATION OF P53 FUNCTION

Background: Epidemiological studies have strongly suggested an association between psychological stress and human cancers. However, this association has not been well established in animal models, and the underlying molecular mechanisms are still unclear. Tumor suppressor p53 plays a central role in tumor prevention. The attenuation or loss of p53 contributes greatly to tumorigenesis. Up until now, the impact of psychological stress upon p53 is poorly understood. Using the mouse model which combines both chronic restraint and irradiation-induced tumorigenesis models, the impact of psychological stress upon tumorigenesis was studied. Interestingly, our preliminary data from a limited number of mice show that chronic restraint promotes gamma irradiation (IR)-induced tumorigenesis in mice. Furthermore, chronic restraint greatly decreases p53 function in mice. It is well known that psychological stress increases the levels of neurohormones, including cortisol and catecholamines. Our preliminary results show that cortisol decreases p53 function. Together, our preliminary results strongly suggest that psychological stress promotes IR-induced tumorigenesis, and the attenuation of p53 function could be an important mechanism, which may be mediated by neurohormones (e.g., cortisol).Objective/Hypothesis: We hypothesize that psychological stress promotes irradiation-induced tumorigenesis, and the attenuation of p53 function could be an important mechanism, which may be mediated by neurohormones, including cortisol.Specific Aims: 1) Investigate and firmly establish the impact of chronic psychological stress upon irradiation-induced tumorigenesis. 2) Test our hypothesis that the attenuation of p53 function is an important mechanism that contributes to chronic restraint-promoted irradiation-induced tumorigenesis. 3) Identify the mechanisms underlying the attenuation of p53 function by chronic restraint, particularly the effect of neurohormones on p53.Study Design: Aim 1: Our preliminary data suggesting that chronic restraint promotes IR-induced tumorigenesis were obtained from a limited number of mice (n=8/group). Here, we will expand this study using additional mice to firmly establish the impact of chronic restraint upon IR-induced tumorigenesis. Furthermore, we will employ ultraviolet (UV) as another source of irradiation to test our hypothesis.Aim 2: We will (1) characterize the change of p53 function in mice with chronic restraint; and (2) investigate whether increasing p53 function by using Nutlin 3a, a specific p53 activator, can block or reduce the effect of chronic restraint on IR-induced tumorigenesis.Aim 3: To test our hypothesis that neurohormones (e.g. cortisol, catecholamines) mediate the inhibitory effect on p53 by chronic restraint, we will determine (1) the effect of cortisol and catecholamines on p53 function in response to IR in cultured cells; (2) the impact of cortisol and catecholamines upon p53 function in response to IR in mice; and (3) whether antagonists of cortisol and catecholamines can block or reduce the inhibitory effect on p53 by chronic restraint in mice.Innovation: The association between psychological stress and cancer has not been well established, and the underlying molecular mechanisms are unclear. In this proposed study, we will (1) test the novel hypothesis that psychological stress promotes irradiation-induced tumorigenesis by using a unique mouse model which combines chronic restraint and irradiation-induced tumorigenesis models; (2) test whether the attenuation of p53 function could be a novel mechanism that contributes to the tumor promotion effects of chronic restraint; and (3) identify the novel mechanisms contributing to the decreased p53 function in chronic restraint. It is our anticipation that this study will greatly increase our understanding of the important relationship between psychological stress, irradiation, and tumorigenesis, and, furthermore, the underlying molecular mechanisms.Impact: Military population is often co-exposed to psychological stress and irradiation (both IR and UV). The investigation on the interactions between psychological stress and irradiation in relation to subsequent tumorigenesis through p53 pathway is of particular importance to military population. It is our anticipation that this study will help to establish the impact of psychological stress upon irradiation-induced tumorigenesis, and greatly increase our understanding of underlying molecular mechanisms. This study will have potential to provide reactivation of p53 pathway as a new strategy to prevent tumorigenesis promoted by psychological stress.