A Constitutive Intrinsic Inflammatory Signaling Circuit Composed of miR-196b, Meis2, PPP3CC, and p65 Drives Prostate Cancer Castration Resistance

Mol Cell. 2017 Jan 5;65(1):154-167. doi: 10.1016/j.molcel.2016.11.034. Epub 2016 Dec 29.

Abstract

Androgen deprivation therapy is the most effective treatment for advanced prostate cancer, but almost all cancer eventually becomes castration resistant, and the underlying mechanisms are largely unknown. Here, we show that an intrinsic constitutively activated feedforward signaling circuit composed of IκBα/NF-κB(p65), miR-196b-3p, Meis2, and PPP3CC is formed during the emergence of castration-resistant prostate cancer (CRPC). This circuit controls the expression of stem cell transcription factors that drives the high tumorigenicity of CRPC cells. Interrupting the circuit by targeting its individual components significantly impairs the tumorigenicity and CRPC development. Notably, constitutive activation of IκBα/NF-κB(p65) in this circuit is not dependent on the activation of traditional IKKβ/NF-κB pathways that are important in normal immune responses. Therefore, our studies present deep insight into the bona fide mechanisms underlying castration resistance and provide the foundation for the development of CRPC therapeutic strategies that would be highly efficient while avoiding indiscriminate IKK/NF-κB inhibition in normal cells.

Keywords: Meis2; NF-κB; PPP3CC; advanced prostate cancer; androgen deprivation therapy; castration-resistance; castration-resistant prostate cancer; constitutively activated inflammatory signaling; miR-196b-3p; stem cell transcription factors; tumorigenicity.

MeSH terms

  • Androgen Antagonists / pharmacology
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Calcineurin / genetics
  • Calcineurin / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Resistance, Neoplasm*
  • Gene Expression Regulation, Neoplastic
  • Genes, myc
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Male
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • NF-KappaB Inhibitor alpha / genetics
  • NF-KappaB Inhibitor alpha / metabolism*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Phenotype
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • RNA Interference
  • Signal Transduction
  • Time Factors
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transfection
  • Tumor Burden
  • Tumor Cells, Cultured

Substances

  • Androgen Antagonists
  • Antineoplastic Agents, Hormonal
  • Homeodomain Proteins
  • MEIS2 protein, human
  • MIRN196 microRNA, human
  • MIRN196 microRNA, mouse
  • MicroRNAs
  • Mrg1 protein, mouse
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • RELA protein, human
  • Rela protein, mouse
  • Transcription Factor RelA
  • Transcription Factors
  • RAG-1 protein
  • NF-KappaB Inhibitor alpha
  • Calcineurin
  • PPP3CC protein, human
  • PPP3CC protein, mouse