Abstract 2961: The N-terminal projection domain of the microtubule associated protein tau inhibits TNFα signaling

Tumor Necrosis Factor-alpha (TNFα) is a multifunctional pro-inflammatory cytokine implicated in inducing both tumor promotion and tumor inhibition. This paradoxical effect can be partly explained by the fact that TNFα acts as a regulator of both proliferation and apoptosis; however the mechanisms and factors associated with how or whether a tumor cell responds to a microenvironment rich in TNFα have not been fully resolved. Here we provide evidence that the microtubule associate protein Tau inhibits TNFα signaling through its N-terminal domain and implicate it as a novel regulator of the cellular response to this key cytokine. Our findings indicate that over-expression of Tau in the human breast cancer cell lines MCF7, SkBr3 and in the pheochromocytoma cell line PC12 suppresses TNFα induced apoptosis evident in the control cells. TNFα induced cell apoptosis in control cells is triggered as early as 6 hrs post-treatment with hallmark features of cell shrinkage, membrane blebbing, disruption of tubulin architecture and caspase-3 activation. While over-expression of wild type full length Tau isoform in these cell lines, completely abrogates all TNFα associated apoptotic phenotypes. Aside from inhibiting TNFα induced apoptosis, Tau over-expression also interferes with TNFα induced NFκB activation. This is evident by a significant decrease in NFκB nuclear translocation in Tau over-expressed cells compared to controls. Suppression of TNFα signaling by Tau is not associated with its tubulin interaction since a truncated N-terminal projection domain lacking all microtubule binding domains still provides resistance to TNFα induced apoptosis and NFκB activation. These findings lead us to conclude that the functional domain of Tau that regulates TNFα response lies within its N-terminal region and current mechanistic studies indicate this region inhibits TNFα receptor clustering, which is needed for signaling. Our data provide direct evidence that the N-terminal domain of the microtubule associated protein Tau can inhibit TNFα signaling in tumor cells. These findings indicate a novel function for Tau and add to our knowledge of how a tumor cell responds to TNFα signaling. Citation Format: Shawon Debnath, Peter Hannon, Kristina Toropova, Nelson Nunez Rodriguez, Alejandra Alonso, Jimmie Eugene Fata. The N-terminal projection domain of the microtubule associated protein tau inhibits TNFα signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2961. doi:10.1158/1538-7445.AM2013-2961 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.