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 | |
| State | Published - May 9 2016 |
ASJC Scopus subject areas
- Oncology
- Cancer Research
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In: Cancer Cell, Vol. 29, No. 5, 09.05.2016, p. 639-652.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
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.
N1 - Funding Information: This work was supported by The MD Anderson Cancer Center SPORE in Multiple Myeloma ( P50 CA142509 ) and The MD Anderson Cancer Center Support Grant ( P30 CA016672 ). L.Y. would like to acknowledge support from the Priority Academic Program Development of Jiangsu Higher Education Institutions and the National Natural Science Foundation of China ( 81272476 ). X.Z. would like to acknowledge support from the National Natural Science Foundation of China ( 81201861 ), and a Research Fellow Award from the Multiple Myeloma Research Foundation . B.B., S.Z.U., Q.Z., and J.C. would like to acknowledge support from the National Cancer Institute ( P01 CA055819 ). S.C. would like to acknowledge support from the Italian Association for Cancer Research (AIRC, Investigator Grant 14691 and Special Program Molecular Clinical Oncology 5 per mille no. 9965). R.Z.O., the Florence Maude Thomas Cancer Research Professor, would also like to acknowledge support from the National Cancer Institute ( U10 CA032102 , R01 CA184464 , CA194264 ), the MD Anderson Cancer Center High Risk Multiple Myeloma Moon Shot , and thank the Brock Family Myeloma Research Fund, the Yates Ortiz Myeloma Fund, the Jay Solomon Myeloma Research Fund, and the Diane & John Grace Family Foundation . G.M., B.L., and D.W.E. are employees of Millennium: The Takeda Oncology Company, which developed and markets bortezomib. R.Z.O. has served on advisory boards for Millennium: The Takeda Oncology Company, which developed and markets bortezomib, and for Onyx Pharmaceuticals , which developed and markets carfilzomib, and has received research support from these firms for other clinical and laboratory projects. B.B. has received research funding from Celgene Corporation and Millennium, is a consultant to Celgene and Millennium, and is a co-inventor on patents and patent applications related to the use of gene-expression profiling in cancer medicine that have been licensed to Myeloma Health, LLC. G.M., B.L., and D.W.E. were employees and shareholders of Takeda Pharmaceuticals USA, Inc., which developed and markets bortezomib. B.B. has received research funding from, and is a research consultant to Takeda Pharmaceuticals USA , Inc., and is a co-inventor on patents and patent applications related to the use of gene-expression profiling in cancer medicine that have been licensed to Signal Genetics. S.Z.U., J.J.S., and R.Z.O. have served on advisory boards for Takeda Pharmaceuticals USA, Inc., and for Amgen, which developed and markets carfilzomib, and S.Z.U. and R.Z.O. have received research funding from these firms. S.Z.U. has served on speaker's bureaus for Takeda Pharmaceuticals USA, Inc., and for Amgen. An abstract describing some of these data was presented at the 55th Annual Meeting of the American Society of Hematology in New Orleans, LA, in December 2013. Funding Information: This work was supported by The MD Anderson Cancer Center SPORE in Multiple Myeloma (P50 CA142509) and The MD Anderson Cancer Center Support Grant (P30 CA016672). L.Y. would like to acknowledge support from the Priority Academic Program Development of Jiangsu Higher Education Institutions and the National Natural Science Foundation of China (81272476). X.Z. would like to acknowledge support from the National Natural Science Foundation of China (81201861), and a Research Fellow Award from the Multiple Myeloma Research Foundation. B.B., S.Z.U., Q.Z., and J.C. would like to acknowledge support from the National Cancer Institute (P01 CA055819). S.C. would like to acknowledge support from the Italian Association for Cancer Research (AIRC, Investigator Grant 14691 and Special Program Molecular Clinical Oncology 5 per mille no. 9965). R.Z.O., the Florence Maude Thomas Cancer Research Professor, would also like to acknowledge support from the National Cancer Institute (U10 CA032102, R01 CA184464, CA194264), the MD Anderson Cancer Center High Risk Multiple Myeloma Moon Shot, and thank the Brock Family Myeloma Research Fund, the Yates Ortiz Myeloma Fund, the Jay Solomon Myeloma Research Fund, and the Diane & John Grace Family Foundation. G.M., B.L., and D.W.E. are employees of Millennium: The Takeda Oncology Company, which developed and markets bortezomib. R.Z.O. has served on advisory boards for Millennium: The Takeda Oncology Company, which developed and markets bortezomib, and for Onyx Pharmaceuticals, which developed and markets carfilzomib, and has received research support from these firms for other clinical and laboratory projects. B.B. has received research funding from Celgene Corporation and Millennium, is a consultant to Celgene and Millennium, and is a co-inventor on patents and patent applications related to the use of gene-expression profiling in cancer medicine that have been licensed to Myeloma Health, LLC. G.M., B.L., and D.W.E. were employees and shareholders of Takeda Pharmaceuticals USA, Inc., which developed and markets bortezomib. B.B. has received research funding from, and is a research consultant to Takeda Pharmaceuticals USA, Inc., and is a co-inventor on patents and patent applications related to the use of gene-expression profiling in cancer medicine that have been licensed to Signal Genetics. S.Z.U., J.J.S., and R.Z.O. have served on advisory boards for Takeda Pharmaceuticals USA, Inc., and for Amgen, which developed and markets carfilzomib, and S.Z.U. and R.Z.O. have received research funding from these firms. S.Z.U. has served on speaker's bureaus for Takeda Pharmaceuticals USA, Inc., and for Amgen. An abstract describing some of these data was presented at the 55th Annual Meeting of the American Society of Hematology in New Orleans, LA, in December 2013. Publisher Copyright: © 2016 Elsevier Inc.
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.
UR - http://www.scopus.com/inward/record.url?scp=84964619858&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964619858&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2016.03.026
DO - 10.1016/j.ccell.2016.03.026
M3 - Article
C2 - 27132469
AN - SCOPUS:84964619858
SN - 1535-6108
VL - 29
SP - 639
EP - 652
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -