title: Calcium blockers decrease the bortezomib resistance in mantle cell lymphoma via manipulation of tissue transglutaminase activities.
abstract: Although bortezomib is clinically approved for the treatment of mantle cell lymphoma (MCL), only limited effects of this treatment have been demonstrated. To improve survival for bortezomib-resistant patients, it is necessary to develop new therapeutic strategies. In the present study, we used biochemical and molecular methodologies to demonstrate that tissue transglutaminase (TG) activates downstream NF-κB signaling pathways. The signaling axis from TG to NF-κB could be a new therapeutic target to overcome bortezomib resistance in MCL. TG2 is a calcium-dependent protein cross-linking enzyme reported to be overexpressed in various cancer cells. We found that MCL cells expressed elevated levels of TG2 and that the modification of TG2 activities altered NF-κB expression and downstream signaling in MCL cells. When TG2 signaling was inhibited by calcium blockers, the combination of a calcium blocker (perillyl alcohol) with bortezomib suppressed NF-κB expression and improved the cytotoxicity of bortezomib in MCL cells. Our study is the first to show the expression of TG2 and the contribution of TG2 to NF-κB signaling in MCL. TG2 inhibition may be used as an alternative target anti-MCL therapy, and calcium blockers may be combined with bortezomib to overcome the bortezomib resistance in MCL.
authors.affiliation: Centre for Stem Cell Research, Brown Foundation Institute of Molecular Medicine for Prevention of Human Diseases, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Jung
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.forename: Luis
authors.initials: L
authors.lastname: Fayad
authors.forename: Jorge
authors.initials: J
authors.lastname: Romaguera
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kwak
authors.forename: Nami
authors.initials: N
authors.lastname: McCarty
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D001897:Boronic Acids / Q000009:adverse effects*; D000069286:Bortezomib; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D039821:Monoterpenes / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D031343:Perilla / Q000737:chemistry; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011719:Pyrazines / Q000009:adverse effects*; D011503:Transglutaminases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D039821:Monoterpenes; D016328:NF-kappa B; D011719:Pyrazines; C032208:perillyl alcohol; D000069286:Bortezomib; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D002118:Calcium