TNF-α inhibits asbestos-induced cytotoxicity via a NF-κB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis

• DOI: 10.1073/pnas.0604008103
• Publication Date: 2006-06-24T00:53:12Z
• Authors: Haining Yang; Maurizio Bocchetta; Barbara Kroczynska; Amira G. Elmishad; Yuanbin Chen; Zemin Liu; Concetta Bubici; Brooke T. Mossman; Harvey I. Pass; Joseph R. Testa; Guido Franzoso; Michele Carbone
• Keywords: Chrysotile; Neoplastic transformation

Asbestos is the main cause of human malignant mesothelioma (MM). In vivo, macrophages phagocytize asbestos and, in response, release TNF-alpha and other cytokines that contribute to carcinogenesis through unknown mechanisms. vitro, does not induce transformation primary mesothelial cells (HM); instead, very cytotoxic HM, causing extensive cell death. This finding raised an apparent paradox: How can MM if HM exposed die? We found induced secretion expression receptor I HM. Treatment with significantly reduced cytotoxicity. Through numerous technical approaches, including chemical inhibitors small interfering RNA strategies, we demonstrate that, activates NF-kappaB activation leads survival resistance effects asbestos. Our data show a critical role for signaling mediating responses NF-kappaB-dependent mechanisms increases percent survives exposure, thus increasing pool asbestos-damaged are susceptible transformation. Cytogenetics supported this hypothesis, showing only rare, aberrant metaphases increased mitotic rate fewer irregular both findings provide mechanistic rationale paradoxical inability transform elucidate underscore pathogenesis humans, identify potential molecular targets anti-MM prevention therapy.