ArticleJournal of experimental & clinical cancer research : CR2018
Inhibition of TPL2 by interferon-α suppresses bladder cancer through activation of PDE4D.
Article in Journal of experimental & clinical cancer research : CR, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
- The multifaceted role of phosphodiesterase 4 in tumor: from tumorigenesis to immunotherapy.Frontiers in immunology · 2025Review
- TPL2 Promotes Gastric Cancer Progression and Chemoresistance Through a Hypoxia-Induced Positive Feedback Loop with PPARδ.International journal of biological sciences · 2025Article
- Bioinformatic Analysis ofInternational journal of molecular sciences · 2024Article
- Predicting bladder cancer survival with high accuracy: insights from MAPK pathway-related genes.Scientific reports · 2024Article
- Elevated PDE4C level serves as a candidate diagnostic biomarker and correlates with poor survival in thyroid carcinoma.Scientific reports · 2024Article
- CRNDE mediated hnRNPA2B1 stability facilitates nuclear export and translation of KRAS in colorectal cancer.Cell death & disease · 2023Article
- Construction of T cell exhaustion model for predicting survival and immunotherapy effect of bladder cancer based on WGCNA.Frontiers in oncology · 2023Article
- Multi-omic characterization of genome-wide abnormal DNA methylation reveals diagnostic and prognostic markers for esophageal squamous-cell carcinoma.Signal transduction and targeted therapy · 2022Article
- Choosing Kinase Inhibitors for Androgen Deprivation Therapy-Resistant Prostate Cancer.Pharmaceutics · 2022Review
- Screening and Validation of a Carvacrol-Targeting Viability-Regulating Protein, SLC6A3, in Liver Hepatocellular Carcinoma.Disease markers · 2022Article
- Construction of an Immune-Autophagy Prognostic Model Based on ssGSEA Immune Scoring Algorithm Analysis and Prognostic Value Exploration of the Immune-Autophagy Gene in Endometrial Carcinoma (EC) Based on Bioinformatics.Journal of healthcare engineering · 2022Article
- Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity.Theranostics · 2020Review
- Type I Interferon (IFN)-Regulated Activation of Canonical and Non-Canonical Signaling Pathways.Frontiers in immunology · 2020Review
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundDrugs that inhibit the MEK/ERK pathway have therapeutic benefit in bladder cancer treatment but responses vary with patients, for reasons that are still not very clear. Interferon-α (IFN-α) is also used as a therapeutic agent for bladder cancer treatment but the response rate is low. It was found that IFN-α could enhance the cytotoxic effect of MEK inhibition. However, the potential mechanisms of that are still unclear. Understanding of the cross-talk between the IFN-α and MEK/ERK pathway will help enhance the efficacy of IFN-α or MEK inhibitors on bladder cancer.
methodsImmunoprecipitation and pull-down assay were used to reveal the formation of signaling complex. The protein expressions were detected by western blot and immunohistochemistry. The cAMP level, Phosphodiesterase 4D (PDE4D) activity and Prostaglandin E
resultsIFN-α down-regulated the cyclooxygenase-2 (COX-2) expression in bladder cancer cells through the inhibition of TPL2/NF-κB pathway; IFN-α also inhibited COX-2 expression by suppressing cAMP signaling through TPL2-ERK mediated PDE4D activity. Reduction of the intracellular cAMP level by PDE4D potentiated the antitumor effect of IFN-α against bladder cancer in vitro and in vivo. Further analysis of clinical samples indicated that low PDE4D expression and high level of TPL2 phosphorylation were correlated to the development and poor prognosis in bladder cancer patients.
conclusionsOur data reveal that IFN-α can exert its antitumor effect through a non-canonical JAK-STAT pathway in the bladder cancer cells with low activity of IFN pathway, and the TPL2 inhibition is another function of IFN-α in the context of bladder cancer therapy. The antitumor effects of IFN-α and MEK inhibition also depend on the PDE4D-mediated cAMP level in bladder cancer cells. Suppression of the TPL2 phosphorylation and intracellular cAMP level may be possible therapeutic strategies for enhancing the effectiveness of IFN-α and MEK inhibitors in bladder cancer treatment.
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