Abstract
Although asbestos causes malignant pleural mesothelioma (MPM), rising from lung mesothelium, the molecular mechanism has not been suggested until now. Extremely low mutation rate in classical tumor suppressor genes (such as p53 and pRb) and oncogenes (including Ras or myc) indicates that there would be MPM-specific carcinogenesis pathway. To address this, we treated silica to mimic mesothelioma carcinogenesis in mesothelioma and non-small cell lung cancer cell lines (NSCLC). Treatment of silica induced p-Erk and Snail through RKIP reduction. In addition, p53 and E-cadherin were decreased by silica-treatment. Elimination of Snail restored p53 expression. We found that NF2 (frequently deleted in MPM) inhibited Snail-mediated p53 suppression and was stabilized by RKIP. Importantly, GN25, an inhibitor of p53-Snail interaction, induced p53 and apoptosis. These results indicate that MPM can be induced by reduction of RKIP/NF2, which suppresses p53 through Snail. Thus, the p53-Snail binding inhibitor such as GN25 is a drug candidate for MPM.
Highlights
Malignant Pleural Mesothelioma (MPM) is asbestosinduced advanced lung cancer with very poor survival rate [1, 2]
We found that NF2 inhibited Snail-mediated p53 suppression and was stabilized by RKIP
GN25, an inhibitor of p53Snail interaction, induced p53 and apoptosis. These results indicate that malignant pleural mesothelioma (MPM) can be induced by reduction of RKIP/NF2, which suppresses p53 through Snail
Summary
Malignant Pleural Mesothelioma (MPM) is asbestosinduced advanced lung cancer with very poor survival rate [1, 2]. Other materials such as silica and nano-carbon tube are considered to be potential tread for MPM [6, 7]. It is generally accepted concept that, to progress to malignant cancer, p53 pathway should be inactivated. MPM shows extremely low genetic mutation rate in p53 and related signaling components such as MDM2 or p14/ARF [8, 14]. This fact indicates that asbestos or silica may inactivate p53 and activate oncogenes through unusual strategy
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