An autoregulatory RelB:p50 NF-B pathway perpetuates pro-survival TNF response in multiple myeloma

Pro-inflammatory cytokines were shown to promote growth and survival of cancerous cells. TNF induced RelA:p50 NF-B dimer via the canonical pathway is thought to link inflammation with cancer. Integrating biochemical and computational studies we identify that deficiency of non-canonical signal transducer p100 triggers a positive autoregulatory loop, which instead perpetuates an alternate RelB:p50 containing NF-B activity upon TNF treatment. TNF stimulated RelB:p50 dimer is sufficient for mediating NF-B target gene-expressions and suppressing apoptotic cellular death independent of principal NF-B subunit RelA. We further demonstrate that activating mutations in non-canonical NF-B module deplete multiple myeloma cells of p100, thereby, provoking autoregulatory RelB:p50 activation. Finally, autoregulatory control reinforces protracted pro-survival NF-B response, albeit comprising of RelB:p50, upon TNF priming that protects myeloma cells with dysfunctional p100 from subsequent apoptotic insults. In sum, we present evidence for positive autoregulation mediated through the NF-B system and its potential involvement in human neoplasm.

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Roy P, Mukherjee T, Chatterjee B, Vijayaragavan B, Banoth B, Basak S