Tight Junction Protein 1 Modulates Proteasome Capacity and Proteasome Inhibitor Sensitivity in Multiple Myeloma via EGFR/JAK1/STAT3 Signaling

Cancer Cell. 2016 May 9;29(5):639-652. doi: 10.1016/j.ccell.2016.03.026. Epub 2016 Apr 28.

Abstract

Proteasome inhibitors have revolutionized outcomes in multiple myeloma, but they are used empirically, and primary and secondary resistance are emerging problems. We have identified TJP1 as a determinant of plasma cell proteasome inhibitor susceptibility. TJP1 suppressed expression of the catalytically active immunoproteasome subunits LMP7 and LMP2, decreased proteasome activity, and enhanced proteasome inhibitor sensitivity in vitro and in vivo. This occurred through TJP1-mediated suppression of EGFR/JAK1/STAT3 signaling, which modulated LMP7 and LMP2 levels. In the clinic, high TJP1 expression in patient myeloma cells was associated with a significantly higher likelihood of responding to bortezomib and a longer response duration, supporting the use of TJP1 as a biomarker to identify patients most likely to benefit from proteasome inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Blotting, Western
  • Bortezomib / pharmacology
  • Bortezomib / therapeutic use
  • Cell Line, Tumor
  • Cysteine Endopeptidases / metabolism
  • Disease-Free Survival
  • ErbB Receptors / metabolism*
  • Erlotinib Hydrochloride / pharmacology
  • Erlotinib Hydrochloride / therapeutic use
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Janus Kinase 1 / metabolism*
  • Mice, SCID
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / pharmacology
  • Proteasome Inhibitors / therapeutic use*
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays / methods
  • Zonula Occludens-1 Protein / genetics
  • Zonula Occludens-1 Protein / metabolism*

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Proteasome Inhibitors
  • STAT3 Transcription Factor
  • TJP1 protein, human
  • Zonula Occludens-1 Protein
  • LMP-2 protein
  • Bortezomib
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors
  • JAK1 protein, human
  • Janus Kinase 1
  • Cysteine Endopeptidases
  • LMP7 protein
  • Proteasome Endopeptidase Complex