Tumor Necrosis Factor α Reduces SNAP29 Dependent Autolysosome Formation to Increase Prion Protein Level and Promote Tumor Cell Migration

Tumor Necrosis Factor alpha (TNF alpha) is best known as a mediator of inflammation and immunity, and also plays important roles in tumor biology. However, the role of TNF alpha in tumor biology is complex and not completely understood. In a human melanoma cell line, M2, and a lung carcinoma cell line, A549, TNF alpha up-regulates prion protein (PrP) level, and promotes tumor cell migration in a PrP dependent manner. Silencing PRNP abrogates TNF alpha induced tumor cell migration; this phenotype is reversed when PRNP is re-introduced. Treatment with TNF alpha activates nuclear factor kappa B (NF-kappa B) signaling, which then mitigates autophagy by reducing the expression of Forkhead Box P3 (FOXP3). Down regulation of FOXP3 reduces the transcription of synaptosome associated protein 29 (SNAP29), which is essential in the fusion of autophagosome and lysosome creating autolysosome. FOXP3 being a bona fide transcription factor for SNAP29 is confirmed in a promoter binding assay. Accordingly, silencing SNAP29 in these cell lines also up-regulates PrP, and promotes tumor cell migration without TNF alpha treatment. But, when SNAP29 or FOXP3 is silenced in these cells, they are no longer respond to TNF alpha. Thus, a reduction in autophagy is the underlying mechanism by which expression of PrP is up-regulated, and tumor cell migration is enhanced upon TNF alpha treatment. Disrupting the TNF alpha-NF-kappa B-FOXP3-SNAP29 signaling axis may provide a therapeutic approach to mitigate tumor cell migration.

Automated summary

TNFα can up-regulate PrP expression and promote tumor cell migration through the TNFα-NF-kappa B-FOXP3-SNAP29 signaling axis. FOXP3 and SNAP29 play critical roles in this process.