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2015 ; 6
(12
): 10073-85
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NF2 blocks Snail-mediated p53 suppression in mesothelioma
#MMPMID25823924
Cho JH
; Lee SJ
; Oh AY
; Yoon MH
; Woo TG
; Park BJ
Oncotarget
2015[Apr]; 6
(12
): 10073-85
PMID25823924
show ga
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.
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