Inflammasome Activator Nigericin Induces Apoptosis in Myeloma cells
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Multiple myeloma (MM) is a neoplastic disorder of plasma cells. Research has shown that cytokines act as a double edged sword in tumour microenvironment to facilitate MM cell homing, survival, proliferation and pathogenesis. Nod like receptors (NLR)s are a specialized group of cytosolic sensors have been associated with increasing number of chronic inflammatory disorders and cancer through induction of proinflammatory cytokines and chemokines, remains poorly defined in multiple meyloma. Initially this project sought to study effect of proinflammatory cytokines and NLR ligands on survival of myeloma. Macrophage inflammatory protein (MIP-1α) and tumour necrosis factor (TNF-α) were found to support cell survival and proliferation, whereas type-1 interferons (Interferon-α and Interferon-β) induced both growth stimulatory and inhibitory effects on different MM cells. The proliferative effects of MIP1α, TNFα and IFNs (IFN-α and β) were more prominent in absence of exogenous IL-6 suggesting that these cytokines may also have supportive role in growth and proliferation of MM cells. Pro- forms of Interleukin-1β (IL-1β) and Interleukin-18 (IL-18) are processed by NLRP3 (NOD-like receptor family, pyrin domain containing-3) inflammasome, a special class of NLR. The inflammatory cytokines IL-1β and IL-18 are elevated in the serum of myeloma patients indicating a possible role of NLR in MM disease progression. In this study, MM cell lines were stimulated with a selection of NLR ligands. The inflammasome activators nigericin and calcium pyrophosphate dehydrate (CPPD) crystals were found to significantly impaired cell survival, measured by decrease in ATP content. Interestingly, nigericin, but not CPPD, induced apoptosis in all the tested MM cell lines. The addition of Interleukin-6 (IL-6) to MM cells treated with nigericin offered no protection against nigericin-induced cell death. Further investigation revealed nigericin-induced caspase-8 activation and caspase-3 cleavage in MM cells. The apoptotic effect of nigericin was furthermore prominent in primary cells from two MM patients. Overall, our data exemplify the role of nigericin as an exogenous modulator of MM cell apoptosis without affecting normal PBMCs, and might be suggested for the first time as a potential therapeutic agent.