Abstract
Abstract Inflammation plays an important role in development of various cancers including malignant mesothelioma (MM). We have shown that asbestos activates NOD-like receptor protein 3 (NLRP3), a component of the inflammasome in human macrophages. As chronic asbestos exposure is a key risk factor for the development of MM, we hypothesized that inflammasome-mediated inflammation might underlie the pathogenesis of this cancer. To show the involvement of NLRP3 in asbestos-induced mesothelioma, we demonstrated that exposure of asbestos to immortalized human mesothelial cells (LP9/hTERT), a cell type responsible for origin of MM, caused mRNA increase and activation of NLRP3 as measured by caspase-1 activation and IL-1β release. Inhibition of NLRP3 by siRNA caused significant decreases in NLRP3 mRNA levels as well as asbestos-induced IL-1β release in medium. On the other hand, human MM lines and tumor tissues showed significantly decreased levels of NLRP3 and caspase-1 as compared to LP9 or matching normal tissues respectively. Our findings suggest that initial exposure to asbestos causes increased mRNA levels and activity of NLRP3, which may help in MM development by promoting mesothelial cell transformation. However, tumor development culminates in MM with decreased NLRP3 protein and increased drug resistance which may be due to caspase-1 inactivation. Thus NLRP3 may be an appropriate target for therapy of MM, especially in combination with cytotoxic chemotherapeutic drugs and IL-1 receptor antagonists. This study is supported by a Meothelioma Applied Research Foundation (MARF) grant (AS) and by NIEHS grants T32 ES07122 (BM). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5461. doi:1538-7445.AM2012-5461
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