Inhibition of TPL2 by interferon-α suppresses bladder cancer through activation of PDE4D

J Exp Clin Cancer Res. 2018 Nov 27;37(1):288. doi: 10.1186/s13046-018-0971-4.


Background: Drugs 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.

Methods: Immunoprecipitation 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 E2 (PGE2) concentration in cells, serum and tissues were detected by enzyme-linked immunosorbent assay. The role of PDE4D in bladder tumorigenesis in vivo was examined by the xenograft model. Tissue microarray chips were used to investigate the prognostic roles of PDE4D and tumor progression locus 2 (TPL2) in bladder cancer patients.

Results: IFN-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.

Conclusions: Our 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.

Keywords: COX-2; Interferon; PDE4D; TPL2; cAMP.

MeSH terms

  • Aminopyridines / pharmacology
  • Animals
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use*
  • Benzamides / pharmacology
  • Cyclic AMP / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Cyclooxygenase 2 / biosynthesis
  • Cyclopropanes / pharmacology
  • Disease Models, Animal
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Female
  • HEK293 Cells
  • Humans
  • Interferon-alpha / pharmacology*
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology


  • Aminopyridines
  • Antiviral Agents
  • Benzamides
  • Cyclopropanes
  • Interferon-alpha
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Roflumilast
  • Cyclic AMP
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • MAP Kinase Kinase Kinases
  • MAP3K8 protein, human
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4D protein, human