Inflammasomes are mediators of inflammation, and constitutively activated NLRP3 inflammasomes have been linked to interleukin-1β (IL-1β)-mediated tumorigenesis in human melanoma. Whereas NLRP3 regulation of caspase-1 activation requires the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD (caspase recruitment domain)), caspase-1 activation by another danger-signaling sensor NLRP1 does not require ASC because NLRP1 contains a C-terminal CARD domain that facilitates direct caspase-1 activation via CARD–CARD interaction. We hypothesized that NLRP1 has additional biological activities besides IL-1β maturation and investigated its role in melanoma tumorigenesis. NLRP1 expression in melanoma was confirmed by analysis of 216 melanoma tumors and 13 human melanoma cell lines. Unlike monocytic THP-1 cells with prominent nuclear localization of NLRP1, melanoma cells expressed NLRP1 mainly in the cytoplasm. Knocking down NLRP1 revealed a tumor-promoting property of NLRP1 both in vitro and in vivo. Mechanistic studies showed that caspase-1 activity, IL-1β production, IL-1β secretion and nuclear factor-kB activity were reduced by knocking down of NLRP1 in human metastatic melanoma cell lines 1205Lu and HS294T, indicating that NLRP1 inflammasomes are active in metastatic melanoma. However, unlike previous reports showing that NLRP1 enhances pyroptosis in macrophages, NLRP1 in melanoma behaved differently in the context of cell death. Knocking down NLRP1 increased caspase-2, -9 and -3/7 activities and promoted apoptosis in human melanoma cells. Immunoprecipitation revealed interaction of NLRP1 with CARD-containing caspase-2 and -9, whereas NLRP3 lacking a CARD motif did not interact with the caspases. Consistent with these findings, NLRP1 activation but not NLRP3 activation reduced caspase-2, -9 and -3/7 activities and provided protection against apoptosis in human melanoma cells, suggesting a suppressive role of NLRP1 in caspase-3/7 activation and apoptosis via interaction with caspase-2 and -9. In summary, we showed that NLRP1 promotes melanoma growth by enhancing inflammasome activation and suppressing apoptotic pathways. Our study demonstrates a tumor-promoting role of NLRP1 in cancer cells.
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We thank the University of Colorado Cancer Center (UCCC) Support Grant (P30CA046934), the Skin Diseases Research Cores Grant (P30AR057212), the Flow Cytometry Core (Christine Childs and Karen Helm) for helping with FACS, and Dr Archana Gopalan (University of Colorado Anschutz Medical Campus) for helping with animal experiments. Imaging experiments were performed in the University of Colorado Anschutz Medical Campus Advance Light Microscopy Core (Radu Moldovan) supported in part by NIH/NCATS Colorado CTSI Grant Number UL1 TR001082. ZZ and JMS are recipients of a training grant, 5T32AR007411-32. This work was supported, in whole or in part, by Veterans Affairs Merit Review Award 5I01BX001228 (to MF), NIH/NCI R01CA197919 (to MF), Cancer League of Colorado (to MF) and NIH/NIAMS 2R01AR045584 (to RAS and MF).
The authors declare no conflict of interest.
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Zhai, Z., Liu, W., Kaur, M. et al. NLRP1 promotes tumor growth by enhancing inflammasome activation and suppressing apoptosis in metastatic melanoma. Oncogene 36, 3820–3830 (2017). https://doi.org/10.1038/onc.2017.26
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