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Multi-walled carbon nanotubes induce apoptosis in normal human small airway epithelial cells through proteasome-mediated McI-1 protein degradation.

Yuan-BZ; Chapman-J; Rojanaskul-Y; Castranova-V; Reynolds-SH
Proceedings of the American Association for Cancer Research (AACR) 101st Annual Meeting, April 17-21, 2010, Washington, D.C. Abstract 3699. Philadelphia, PA: American Association for Cancer Research, 2010 Apr; 51:898-899
Engineered carbon nanotubes (CNTs) are emerging as the major building blocks in nanotechnology thanks to their unique physical and chemical properties. However, widespread application of CNTs, including single- and mulit-walled (SWCNTs and MWCNT), has resulted in increased public concern regarding potential toxicities from occupational or environmental exposures to CNTs. Recently, both SWCNTs and MWCNTs have been observed to exhibit pulmonary toxicities. To better understand CNT-related pulmonary toxicities, the present in vitro study used normal human small airway epithelial cells (SAEC), which constitute a primary target of respiratory exposure to CNTs, as a model to investigate cell death effects of either SWCNTs or MWCNTs. We observed that, at 24 h after exposure, greater than 5 microg/cm2 MWCNT, but not SWCNT, induced a significant dose-dependent cell death in primary cultured SAEC cells as assayed by WST-1. The cell death was accompanied by DNA damage, as indicated by the appearance of sub G0/G1 cells in a flow cytomtery assay, and protein cleavages for PARP, caspases 3, 7 and 9, as revealed by Western blotting. It was further observed that the proaporpotic activities of WMCNT were reduced by caspase specific inhibitors, demonstrating that MWCNT, but not SWCNT, can induce a caspase-dependent apoptosis in SAEC cells. To understand regulation of the WMCNT-induced apoptosis, we then examined expression of the anti-apoptotic Bcl-2 family proteins and found that only Mcl-1 was significantly reduced in protein level by MWCNT, but not SWCNT, and such reduction was blocked by proteasome inhibitor MG132. Furthermore, it was found that reduction of Mcl-1 protein expression through Mcl-1 siRNA enhanced sensitivity of SAEC cells to MWCNT-induced apoptosis, suggesting that proteasome-mediated Mcl-1 protein degradation contributes to MWCNT-induced apoptosis. This study reveals a difference in cell death effects on normal human SAEC cells between SWCNT and MWCNT. It also provides new insights into understanding of the MWCNT-induced pulmonary toxicity.
Cancer; Lung-cancer; Reproductive-system-disorders; Pulmonary-system-disorders; Cellular-reactions; Cellular-function; Cell-damage; Cell-function; DNA-damage; Nanotechnology; Proteins
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Proceedings of the American Association for Cancer Research (AACR) 101st Annual Meeting, April 17-21, 2010, Washington, DC