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 Wang; Jiexin 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

doi:10.1016/j.ccell.2016.03.026

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

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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 language	English (US)
Pages (from-to)	639-652
Number of pages	14
Journal	Cancer Cell
Volume	29
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2016.03.026
State	Published - May 9 2016

ASJC Scopus subject areas

Oncology
Cancer Research

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Zhang, X. D., Baladandayuthapani, V., Lin, H., Mulligan, G., Li, B., Esseltine, D. L. W., Qi, L., Xu, J., Hunziker, W., Barlogie, B., Usmani, S. Z., Zhang, Q., Crowley, J., Hoering, A., Shah, J. J., Weber, D. M., Manasanch, E. E., Thomas, S. K., Li, B. Z., ... Orlowski, R. Z. (2016). Tight Junction Protein 1 Modulates Proteasome Capacity and Proteasome Inhibitor Sensitivity in Multiple Myeloma via EGFR/JAK1/STAT3 Signaling. Cancer Cell, 29(5), 639-652. https://doi.org/10.1016/j.ccell.2016.03.026

Zhang, XD, Baladandayuthapani, V, Lin, H, Mulligan, G, Li, B, Esseltine, DLW, Qi, L, Xu, J, Hunziker, W, Barlogie, B, Usmani, SZ, Zhang, Q, Crowley, J, Hoering, A, Shah, JJ, Weber, DM, Manasanch, EE, Thomas, SK, Li, BZ, Wang, HH, Zhang, J, Kuiatse, I, Tang, JL, Wang, H, He, J, Yang, J, Milan, E, Cenci, S, Ma, WC, Wang, ZQ, Davis, RE, Yang, L & Orlowski, RZ 2016, 'Tight Junction Protein 1 Modulates Proteasome Capacity and Proteasome Inhibitor Sensitivity in Multiple Myeloma via EGFR/JAK1/STAT3 Signaling', Cancer Cell, vol. 29, no. 5, pp. 639-652. https://doi.org/10.1016/j.ccell.2016.03.026

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = may,

day = "9",

doi = "10.1016/j.ccell.2016.03.026",

language = "English (US)",

volume = "29",

pages = "639--652",

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T1 - Tight Junction Protein 1 Modulates Proteasome Capacity and Proteasome Inhibitor Sensitivity in Multiple Myeloma via EGFR/JAK1/STAT3 Signaling

AU - Zhang, Xing Ding

AU - Baladandayuthapani, Veerabhadran

AU - Lin, Heather

AU - Mulligan, George

AU - Li, Bin

AU - Esseltine, Dixie Lee W.

AU - Qi, Lin

AU - Xu, Jianliang

AU - Hunziker, Walter

AU - Barlogie, Bart

AU - Usmani, Saad Z.

AU - Zhang, Qing

AU - Crowley, John

AU - Hoering, Antje

AU - Shah, Jatin J.

AU - Weber, Donna M.

AU - Manasanch, Elisabet E.

AU - Thomas, Sheeba K.

AU - Li, Bing Zong

AU - Wang, Hui Han

AU - Zhang, Jiexin

AU - Kuiatse, Isere

AU - Tang, Jin Le

AU - Wang, Hua

AU - He, Jin

AU - Yang, Jing

AU - Milan, Enrico

AU - Cenci, Simone

AU - Ma, Wen Cai

AU - Wang, Zhi Qiang

AU - Davis, Richard Eric

AU - Yang, Lin

AU - Orlowski, Robert Z.

PY - 2016/5/9

Y1 - 2016/5/9

N2 - 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.

AB - 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.

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JF - Cancer Cell

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

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