Carbon nanotubes induce apoptosis resistance through FLICE-inhibitory protein.
Pongrakhananon-V; Lu-Y; Wang-L; Stueckle-T; Luanpitpong-S; Rojanasakul-Y
Toxicologist 2011 Mar; 120(Suppl 2):254
Our studies have shown that chronic exposure to single-walled carbon nanotubes (SWCNT) induces apoptosis resistance and malignant transformation of human lung epithelial cells. Since resistance to apoptosis is a foundation of neoplastic evolution and selection of malignant transformed phenotype, we investigated the apoptosis pathway underlying the resistance its mechanisms to aid the understanding of SWCNT-induced carcinogenesis. As compared to passage-matched control cells, SWCNT-transformed BEAS-2B cells exhibited resistance to apoptosis induced by death ligands, e.g., tumor necrosis factor-a and Fas ligand, but not by inducers of mitochondria-mediated apoptosis, e.g., antimycin A and cisplatin, suggesting death receptor pathway as the primary pathway of defective apoptosis in SWCNT-transformed cells. The results were confirmed using caspase specific inhibitors and caspase activity assays. DNA microarray and Western blot analyses of key apoptosis-regulatory proteins in the transformed cells revealed FLICE-inhibitory protein (FLIP) as an important target of regulation by SWCNT. Overexpression of FLIP increased apoptosis resistance of the cells, whereas RNAi knockdown of FLIP reversed the apoptosis resistance of cells in response to death ligands. Together, our study demonstrated a novel mechanism of apoptosis resistance induced by chronic exposure to SWCNT in human lung epithelial cells and identified FLIP as a key regulator of apoptosis avoidance that contributes to the development of malignant transformed phenotype.
Biological-effects; Cancer; Carcinogenicity; Cell-biology; Cell-function; Cell-metabolism; Cell-morphology; Cell-transformation; Cellular-reactions; Exposure-assessment; Inhalation-studies; Laboratory-testing; Lung-cancer; Lung-cells; Lung-disease; Lung-disorders; Lung-irritants; Nanotechnology; Physiological-effects; Pulmonary-function; Pulmonary-system; Pulmonary-system-disorders; Quantitative-analysis; Respiratory-hypersensitivity; Respiratory-irritants; Respiratory-system-disorders; Risk-analysis; Risk-factors; Statistical-analysis
The Toxicologist. Society of Toxicology 50th Annual Meeting and ToxExpo, March 6-10, 2011, Washington, DC