TRANSCRIPTION FACTOR NFKB IN LUNG CANCER DEVELOPMENT

University Of Texas Md Anderson Can Ctr, Houston TX

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Abstract

DESCRIPTION (provided by applicant): Cigarette smoke (CS) causes approximately 80-90 percent of lung cancer in the United States, but the mechanism by which CS mediates its effects is not fully understood. One factor may be transcription factor NF-kB, which regulates the expression of various genes involved in tumor initiation, promotion, and metastasis. We hypothesize that NF-kB activation by CS is an important factor in lung cancer development, and that inhibition of NF-kB activation or the activity of NF-kB regulated gene products (such as cyclooxygenase-2) could prevent lung cancer development. To test this hypothesis, we propose the following specific aims: Specific Aim 1: Determine if NF-kB is activated in biopsies containing bronchial epithelial cells from former and current cigarette smokers before and after celecoxib treatment. Specific Aim 2: Determine if cigarette smoke activates NF-kB and induces the NF-kB dependent gene expression in selected normal, premalignant and malignant lung cancer cell lines. Specific Aim 3: Determine if the cigarette smoke-induced NF-kB activation blocks apoptosis. Specific Aim 4: Determine if celecoxib downregulates cigarette smoke-induced NF-kB activation and overcomes cigarette smoke-induced resistance to apoptosis. Through these studies, we will determine: 1) whether cigarette smoking in humans leads to NF-kB activation and if it is modulated by celecoxib; 2) whether cigarette smoke activates NF-kB and induces NF-kB-dependent gene expression in bronchial epithelial lung cells; 3) whether CS-induced NF-kB results in suppression of apoptosis; and, 4) whether celecoxib can induce apoptosis through suppression of CS-induced NF-kB activation.