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Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells.

ABSTRACT: Diversity within the p53 transcriptional network can arise from a matrix of changes that include target response element sequences and p53 expression level variations. We previously found that wild type p53 (WT p53) can regulate expression of most innate immune-related Toll-like-receptor genes (TLRs) in human cells, thereby affecting immune responses. Since many tumor-associated p53 mutants exhibit change-of-spectrum transactivation from various p53 targets, we examined the ability of twenty-five p53 mutants to activate endogenous expression of the TLR gene family in p53 null human cancer cell lines following transfection with p53 mutant expression vectors. While many mutants retained the ability to drive TLR expression at WT levels, others exhibited null, limited, or change-of-spectrum transactivation of TLR genes. Using TLR3 signaling as a model, we show that some cancer-associated p53 mutants amplify cytokine, chemokine and apoptotic responses after stimulation by the cognate ligand poly(I:C). Furthermore, restoration of WT p53 activity for loss-of-function p53 mutants by the p53 reactivating drug RITA restored p53 regulation of TLR3 gene expression and enhanced DNA damage-induced apoptosis via TLR3 signaling. Overall, our findings have many implications for understanding the impact of WT and mutant p53 in immunological responses and cancer therapy.

SUBMITTER: Menendez D

PROVIDER: S-EPMC5308678 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells.

Menendez Daniel D Lowe Julie M JM Snipe Joyce J Resnick Michael A MA

Oncotarget 20160901 38

Diversity within the p53 transcriptional network can arise from a matrix of changes that include target response element sequences and p53 expression level variations. We previously found that wild type p53 (WT p53) can regulate expression of most innate immune-related Toll-like-receptor genes (TLRs) in human cells, thereby affecting immune responses. Since many tumor-associated p53 mutants exhibit change-of-spectrum transactivation from various p53 targets, we examined the ability of twenty-fiv ...[more]

PMID: 27533082

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Project description:BackgroundToll-like receptor 3 (TLR3) ligand which activates TLR3 signaling induces both cancer cell death and activates anti-tumor immunity. However, TLR3 signaling can also harbor pro-tumorigenic consequences. Therefore, we examined the status of TLR3 in cholangiocarcinoma (CCA) cases to better understand TLR3 signaling and explore the potential therapeutic target in CCA.MethodsThe expression of TLR3 and receptor-interacting protein kinase 1 (RIPK1) in primary CCA tissues was assayed by Immunohistochemical staining and their associations with clinicopathological characteristics and survival data were evaluated. The effects of TLR3 ligand, Poly(I:C) and Smac mimetic, an IAP antagonist on CCA cell death and invasion were determined by cell death detection methods and Transwell invasion assay, respectively. Both genetic and pharmacological inhibition of RIPK1, RIPK3 and MLKL and inhibitors targeting NF-κB and MAPK signaling were used to investigate the underlying mechanisms.ResultsTLR3 was significantly higher expressed in tumor than adjacent normal tissues. We demonstrated in a panel of CCA cell lines that TLR3 was frequently expressed in CCA cell lines, but was not detected in a nontumor cholangiocyte. Subsequent in vitro study demonstrated that Poly(I:C) specifically induced CCA cell death, but only when cIAPs were removed by Smac mimetic. Cell death was also switched from apoptosis to necroptosis when caspases were inhibited in CCA cells-expressing RIPK3. In addition, RIPK1 was required for Poly(I:C) and Smac mimetic-induced apoptosis and necroptosis. Of particular interest, high TLR3 or low RIPK1 status in CCA patients was associated with more invasiveness. In vitro invasion demonstrated that Poly(I:C)-induced invasion through NF-κB and MAPK signaling. Furthermore, the loss of RIPK1 enhanced Poly(I:C)-induced invasion and ERK activation in vitro. Smac mimetic also reversed Poly(I:C)-induced invasion, partly mediated by RIPK1. Finally, a subgroup of patients with high TLR3 and high RIPK1 had a trend toward longer disease-free survival (p = 0.078, 28.0 months and 10.9 months).ConclusionRIPK1 plays a pivotal role in TLR3 ligand, Poly(I:C)-induced cell death when cIAPs activity was inhibited and loss of RIPK1 enhanced Poly(I:C)-induced invasion which was partially reversed by Smac mimetic. Our results suggested that TLR3 ligand in combination with Smac mimetic could provide therapeutic benefits to the patients with CCA. Video abstract.

Dataset Information

Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells.

Publications

Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells.

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