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Regulation of TAK1/TAB1-mediated IL-1? signaling by cytoplasmic PPAR?/?.

ABSTRACT: The peroxisome proliferator-activated receptor subtypes PPAR?, PPAR?/?, PPAR? are members of the steroid hormone receptor superfamily with well-established functions in transcriptional regulation. Here, we describe an unexpected cytoplasmic function of PPAR?/?. Silencing of PPAR?/? expression interferes with the expression of a large subset of interleukin-1? (IL-1?)-induced target genes in HeLa cells, which is preceded by an inhibition of the IL-1?-induced phosphorylation of TAK1 and its downstream effectors, including the NF?B? inhibitor I?B? (NFKBIA) and the NF?B? subunit p65 (RELA). PPAR?/? enhances the interaction between TAK1 and the small heat-shock protein HSP27, a known positive modulator of TAK1-mediated IL-1? signaling. Consistent with these findings, PPAR?/? physically interacts with both the endogenous cytoplasmic TAK1/TAB1 complex and HSP27, and PPAR?/? overexpression increases the TAK1-induced transcriptional activity of NF?B. These observations suggest that PPAR?/? plays a role in the assembly of a cytoplasmic multi-protein complex containing TAK1, TAB1, HSP27 and PPAR?/?, and thereby participates in the NF?B response to IL-1?.

SUBMITTER: Stockert J

PROVIDER: S-EPMC3639976 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Regulation of TAK1/TAB1-mediated IL-1β signaling by cytoplasmic PPARβ/δ.

Stockert Josefine J Wolf Alexander A Kaddatz Kerstin K Schnitzer Evelyn E Finkernagel Florian F Meissner Wolfgang W Müller-Brüsselbach Sabine S Kracht Michael M Müller Rolf R

PloS one 20130430 4

The peroxisome proliferator-activated receptor subtypes PPARα, PPARβ/δ, PPARγ are members of the steroid hormone receptor superfamily with well-established functions in transcriptional regulation. Here, we describe an unexpected cytoplasmic function of PPARβ/δ. Silencing of PPARβ/δ expression interferes with the expression of a large subset of interleukin-1β (IL-1β)-induced target genes in HeLa cells, which is preceded by an inhibition of the IL-1β-induced phosphorylation of TAK1 and its downstr ...[more]

PMID: 23646170

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Project description:Intraperitoneal metastasis is a common occurrence and is usually involved in the poor prognosis of ovarian cancer. Its specific metastatic pattern implies that certain indispensable microenvironmental factors secreted in the peritoneal cavity can direct metastatic ovarian cancer cells to permissive niches for secondary lesion formation. However, the underlying molecular mechanisms are ill defined. Herein, we report that GRO-α and IL-8 are predominately upregulated in culture media derived from either normal or cancerous omenta and are associated with increased ovarian cancer aggressiveness. Methods: OCM was established from culture medium of fresh human omental tissues. Primary and metastatic ovarian cancer cell lines were generated from human tumor tissues and verified by specific antibodies. The functional roles of GRO-α, IL-8, and their specific receptor CXCR2 were examined by neutralizing antibodies, shRNA gene knockdown, CRISPR/Cas9 gene knockout and pharmaceutical CXCR2 inhibitor SB225002. The oncogenic properties of ovarian cancer cells were examined by in vitro and in vivo mouse models. Results: Both GRO-α and IL-8 can activate TAK1/NFκB signaling via the CXCR2 receptor. Intriguingly, TAK1/NFκB signaling activity was higher in metastatic ovarian cancer cells; this higher activity makes them more susceptible to OCM-induced tumor aggressiveness. Treatment of ovarian cancer cells with GRO-α and IL-8 neutralizing antibodies or ablation of CXCR2 by shRNA gene knockdown, CRISPR/Cas9 gene knockout, or CXCR2 inhibitor SB225002 treatment significantly attenuated TAK1/NFκB signaling and decreased in vitro and in vivo oncogenic and metastatic potential, suggesting CXCR2 plays a key role in the GRO-α and IL-8-governed metastatic spreading of ovarian cancer cells in the intraperitoneal cavity. Conclusion: This study highlights the significance of GRO-α and IL-8 as the key chemokines in the peritoneal tumor microenvironment and suggests the utility of targeting their receptor CXCR2 as a potential target-based therapy for peritoneal metastases of ovarian cancer.

Dataset Information

Regulation of TAK1/TAB1-mediated IL-1? signaling by cytoplasmic PPAR?/?.

Publications

Regulation of TAK1/TAB1-mediated IL-1β signaling by cytoplasmic PPARβ/δ.

Similar Datasets

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