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.
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu 215123, China; Xi'an Jiaotong University Suzhou Academy, Suzhou, Jiangsu 215123, China.
authors.forename: Xing-Ding
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Veerabhadran
authors.initials: V
authors.lastname: Baladandayuthapani
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Lin
authors.affiliation: Millennium: The Takeda Oncology Company, Cambridge, MA 02139, USA.
authors.forename: George
authors.initials: G
authors.lastname: Mulligan
authors.affiliation: Millennium: The Takeda Oncology Company, Cambridge, MA 02139, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Millennium: The Takeda Oncology Company, Cambridge, MA 02139, USA.
authors.forename: Dixie-Lee W
authors.initials: DW
authors.lastname: Esseltine
authors.affiliation: Xi'an Jiaotong University Suzhou Academy, Suzhou, Jiangsu 215123, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Qi
authors.affiliation: Institute of Molecular and Cell Biology, Singapore 138673, Republic of Singapore.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Xu
authors.affiliation: Institute of Molecular and Cell Biology, Singapore 138673, Republic of Singapore.
authors.forename: Walter
authors.initials: W
authors.lastname: Hunziker
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Department of Hematologic Oncology, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC 28204, USA.
authors.forename: Saad Z
authors.initials: SZ
authors.lastname: Usmani
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Department of Hematologic Oncology, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC 28204, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Cancer Research and Biostatistics, Seattle, WA 98101, USA.
authors.forename: John
authors.initials: J
authors.lastname: Crowley
authors.affiliation: Cancer Research and Biostatistics, Seattle, WA 98101, USA.
authors.forename: Antje
authors.initials: A
authors.lastname: Hoering
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jatin J
authors.initials: JJ
authors.lastname: Shah
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Weber
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Elisabet E
authors.initials: EE
authors.lastname: Manasanch
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sheeba K
authors.initials: SK
authors.lastname: Thomas
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Bing-Zong
authors.initials: BZ
authors.lastname: Li
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hui-Han
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jiexin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Isere
authors.initials: I
authors.lastname: Kuiatse
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Jin-Le
authors.initials: JL
authors.lastname: Tang
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele, Milan 20132, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Milan
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Università Vita-Salute San Raffaele, Milan 20132, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Cenci
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wen-Cai
authors.initials: WC
authors.lastname: Ma
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Wang
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Richard Eric
authors.initials: RE
authors.lastname: Davis
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, Jiangsu 215123, China; Xi'an Jiaotong University Suzhou Academy, Suzhou, Jiangsu 215123, China. Electronic address: yanglin@suda.edu.cn.
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rorlowsk@mdanderson.org.
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism*; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D061988:Proteasome Inhibitors; D050796:STAT3 Transcription Factor; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; C071313:LMP-2 protein; D000069286:Bortezomib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex