Role of TNFα and leptin signaling in colon cancer incidence and tumor growth under obese phenotype

Epidemiological studies over the last few decades have shown a strong influence of obesity on colon cancer risk and its progression. These studies have primarily focussed on the role of adipokines in driving cancer progression. We investigated the incidence of cancerous polyp formation and tumor progression in presence and absence of functional leptin along with exploring the role of tumor necrosis factor alpha (TNF alpha), under obese condition. By utilizing diet induced obese and genetically obese mice, carcinogen induced colon polyp formation was investigated. Experiments were performed using tumor tissues and cell lines to delineate the inter-relationship between leptin and TNF alpha. Data shown in this report indicates that in leptin knockdown obese mice, AOM/DSS induced polyps are smaller and lesser in numbers as compared to AOM/DSS induced polyps in diet induced obese mice. Further in vitro experiments suggest that abrogation of leptin associated pathways promote TNF alpha induced apoptosis. Mechanistically, we report that TNF alpha induces p53 independent cell death through up regulation of p53 upregulated modulator of apoptosis (PUMA). TNF alpha induced PUMA was inhibited upon preexposure of cells to leptin, prior to TNF alpha treatment. Collectively these results indicate that obesity due to leptin non-functionality facilitates TNF alpha induced colon cancer cell death.