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

Xing Ding Zhang, Veerabhadran Baladandayuthapani, Heather Lin, George Mulligan, Bin Li, Dixie Lee W. Esseltine, Lin Qi, Jianliang Xu, Walter Hunziker, Bart Barlogie, Saad Z. Usmani, Qing Zhang, John Crowley, Antje Hoering, Jatin J. Shah, Donna M. Weber, Elisabet E. Manasanch, Sheeba K. Thomas, Bing Zong Li, Hui Han WangJiexin Zhang, Isere Kuiatse, Jin Le Tang, Hua Wang, Jin He, Jing Yang, Enrico Milan, Simone Cenci, Wen Cai Ma, Zhi Qiang Wang, Richard Eric Davis, Lin Yang, Robert Z. Orlowski

    Research output: Contribution to journalArticlepeer-review

    75 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)639-652
    Number of pages14
    JournalCancer Cell
    Volume29
    Issue number5
    DOIs
    StatePublished - May 9 2016

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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