Regulation of Par-4 Secretion in Normal Cells for Paracrine Action in Tumor Cells

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DESCRIPTION (provided by applicant): Lung cancer is a leading cause of cancer death in men and women in the United States. Mutations leading to activation of the Ras oncogenes and inactivation of the p53 tumor suppressor gene are two of the most common alterations in lung cancer. As the tumor growth inhibitory action of chemotherapy and radiation therapy generally requires wild-type p53 function, lung tumors with p53 mutations or deletions develop resistance to therapy resulting in ultimate death of the patients. Moreover, oncogenic Ras activation and p53 inactivation results in elevated NF-kB activity that contributes to cell survival and therapeutic resistance. Tumor growth is regulated by a complex network of interactions between normal cells and cancer cells. In addition to local interactions, tumor growth may be influenced by growth-promoting and growth-inhibiting factors produced systemically by the host. Accordingly, cancer therapeutics can be aptly utilized to regulate the systemic environment in order to directly target aberrant growth. Understanding the mechanisms associated with systemic secretion of pro-apoptotic proteins by normal cells and their effect on tumor epithelial cells is a critical facet of such investigations. A majority of the cells throughout the body of lug cancer patients are normal and have wild type p53 status. This proposal will explore whether p53 activation in normal cells triggers paracrine cell death in p53-deficient lung tumors. As p53 activation only partially inhibits NF-kB activity, our Preliminary Studies used co-parallel activation of p53 and inhibition of NF-kB in normal cells to identify secreted protein(s) that can cause a paracrine apoptotic effect in p53-deficient lung cancer cells. Based on our findings, we hypothesize that p53 regulates the secretion of the pro-apoptotic tumor suppressor protein Par-4 from normal cells for paracrine effect in cancer cells, and that maximum induction of Par-4 protein by p53 activation and NF-kB inhibition from normal cells should effectively induce apoptosis in p53-deficient lung tumors in mice. The proposed study will explore the feasibility of this novel area of investigation by pursuing two Specific Aims. (Aim 1) Determine the mechanism by which p53 activation in normal cells induces tumor cell apoptosis. We will study the kinetics and mechanism of Par-4 secretion induced by p53 in diverse normal cell types leading to apoptosis of p53-deficient lung cancer cells. (Aim 2) Determine the paracrine effect of Par-4 secretion, which is induced by p53 activation in normal cells, on p53-deficient lung tumors. After concomitant activation of p53 and inhibition of NF-kB activity, we will test the kinetics of systemic elevation of Par-4 protein and its effect on apoptosis and regression of lung tumors in K-rasLSL-G12D,p53Fl/Fl mice. Moreover, mechanistic studies will be undertaken to gain deeper insights into the functional role of Par-4 in the paracrine action on these tumors in mice. Collectively, these studies will uncover the feasibility and mechanism of the paracrine effects of p53 activation in normal cells for apoptosis and regression of p53-deficient lung cancer. As p53 is mutated in diverse cancers, the findings of this study will have broad translational implications.