Potential role of ferritin heavy chain in oxidative stress and apoptosis in human mesothelial and mesothelioma cells: implications for asbestos-induced oncogenesis

Carcinogenesis. 2007 Apr 13; [Epub ahead of print] [Link]

Winn Aung, Sumitaka Hasegawa^*, Takako Furukawa and Tsuneo Saga

Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan

^* Corresponding author: Sumitaka Hasegawa, MD. Ph.D., Diagnostic Imaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-ku, Chiba 263-8555, Japan, Tel: +81-43-206-3380, Fax: +81-43-206-0818, E-mail: shase@nirs.go.jp

Abstract

Exposure to asbestos is a known etiological factor in malignant mesothelioma (MM). However, in vitro cell culture studies have provided paradoxical evidence that asbestos exposure to mesothelial cells causes cytotoxicity or apoptosis rather than malignant transformation. Although it has been shown that the iron associated with asbestos participates in the cell toxicity and likely MM pathogenesis via generation of reactive oxygen species (ROS), the molecular mechanism(s) largely remains unknown. Here we demonstrate that ferritin heavy chain (FHC), a core subunit of iron-binding protein ferritin, works as an anti-apoptotic protein against toxic asbestos and oxidative stress in human mesothelial cells and MM cells. We found that FHC was induced in asbestos-exposed MeT-5A human mesothelial cells. The mesothelial cell line stably expressing FHC generated less amount of hydrogen peroxide (H₂O₂), one of the main ROS, after asbestos exposure and was more resistant to apoptosis induced by H₂O₂ compared with the cells transfected with the empty vector. Next, we investigated biological roles of FHC in human MM cell. We found that NCI-H2052, a human MM cell line, had a higher expression of endogenous FHC than MeT-5A and used the cell to address FHC function in MM. NCI-H2052 showed reduced H₂O₂ production and an apoptosis resistant phenotype compared to MeT-5A. Suppression of the over-expressed FHC by using FHC siRNA rendered the MM cells sensitive to apoptosis, suggesting the contribution of FHC to apoptosis resistance of the MM cells. Our findings highlight the potential role of FHC in the pathogenesis of asbestos-induced mesothelioma.