Biological Chemistry of Reactive Nitrogen Species Signaling in Cancer Etiology

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DESCRIPTION (provided by applicant): Nitric oxide (NO) is one of the smallest molecules in Nature and has recently been discovered to play important roles in a remarkable array of physiological and pathophysiological phenomena. In spite of the fact that it is extremely small, as cellular molecules go, its actions are multiple and not well understood. In many cases, its actions are "Janus-faced", performing either harmful or helpful actions. What controls this contradictory behavior is unknown. We propose to study one important role of NO, as a messenger molecule that initiates signaling cascades resulting in appropriate responses of the cell. NO has been proposed to effect a variety of signaling mechanisms, and we have chosen to examine the roles of NO in tumor development. NO is well- known to possess pro-cancerous and also anti-cancerous actions. We will apply a new theoretical approach to this problem, which makes specific and testable predictions. Our studies will range from test-tube chemistry of simple small molecules to isolated signaling proteins to the activation of these proteins in cells and finally the importance of NO signaling in an animal tumor model. We hope to develop a biochemical "road map" that could navigate design of specific therapeutic modalities to allow intelligent manipulation of prevailing in vivo chemical conditions and/or protein responses and effect redirection of the "pro-cancerous" biological actions toward the "anti- cancerous". PUBLIC HEALTH RELEVANCE: The research we will carry out is directed to understand the mechanisms between cells that orchestrate the development of Cancer. Our overall approach is to try to understand the chemistry that determines signaling by the very small and reactive molecule nitric oxide (NO). Our experimental systems will span "test-tube" studies with small molecules to cells and proteins and finally to studies using a tumor model in mice. Insights we obtain may form the basis for the development of new therapies for cancer.