title: Parathyroid hormone receptor mediates the anti-myeloma effect of proteasome inhibitors.
abstract: Clinically significant serum parathyroid hormone (PTH) variations have been reported in multiple myeloma (MM) patients treated with proteasome inhibitors. To elucidate the association between serum PTH variations and proteasome inhibition in MM, the effect of PTH and PTHR1 ligands on the proteasome inhibitors bortezomib and carfilzomib in vitro and in vivo was determined. The MM cell lines ARP1, OC1 and 5TGM1 expressed mRNA and protein encoding PTH receptor 1 (PTHR1). Treatment of 5TGM1 cells with either PTH(1-34), bortezomib or carfilzomib alone dose-dependently inhibited 5TGM1 cell proliferation. However, treatment with the potent PTHR1 antagonist [TYR34]PTH(7-34) (PTH(7-34)) had no significant effect on myeloma cell proliferation and cell viability. In contrast, when used in combination with bortezomib or carfilzomib, PTH(7-34) treatment significantly reduced the bortezomib or carfilzomib-associated decrease in cell proliferation. Treatment of the C57BL/KaLwRij mouse myeloma model with either bortezomib or carfilzomib provided a significantly prolonged survival benefit compared to controls (p=0.04; p=0.01 respectfully). This potent anti-myeloma effect was completely abrogated by concomitant treatment with PTH(7-34). These results suggest an important role of the PTHR1 in the anti-myeloma effect of proteosome inhibition.
authors.affiliation: University of Utah, Myeloma Program, Salt Lake City, UT, USA. Electronic address: mzangari2@uams.edu.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Zangari
authors.affiliation: University of Padua, Italy. Electronic address: tamara.berno@unipd.it.
authors.forename: Tamara
authors.initials: T
authors.lastname: Berno
authors.affiliation: University of Utah, Myeloma Program, Salt Lake City, UT, USA. Electronic address: ye.yang@hsc.utah.edu.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yang
authors.affiliation: University of Utah, Myeloma Program, Salt Lake City, UT, USA. Electronic address: ming.zeng@hsc.utah.edu.
authors.forename: Ming
authors.initials: M
authors.lastname: Zeng
authors.affiliation: University of Utah, Myeloma Program, Salt Lake City, UT, USA. Electronic address: hongwei.xu@hsc.utah.edu.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Xu
authors.affiliation: Huntsman Cancer Institute, Salt Lake City, UT, USA. Electronic address: lisa.pappas@hci.utah.edu.
authors.forename: Lisa
authors.initials: L
authors.lastname: Pappas
authors.affiliation: University of Utah, Myeloma Program, Salt Lake City, UT, USA. Electronic address: guido.tricot@hsc.utah.edu.
authors.forename: Guido
authors.initials: G
authors.lastname: Tricot
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: akamalakar@uams.edu.
authors.forename: Archana
authors.initials: A
authors.lastname: Kamalakar
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: DYoon@uams.edu.
authors.forename: Donghoon
authors.initials: D
authors.lastname: Yoon
authors.affiliation: Department of Orthopaedic Surgery, Center for Orthopaedic Research, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Electronic address: suvalarryj@uams.edu.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Suva
mesh_terms: D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism*
chemical_list: D001897:Boronic Acids; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D011719:Pyrazines; D044168:Receptor, Parathyroid Hormone, Type 1; D000069286:Bortezomib; C524865:carfilzomib
keywords: Multiple myeloma; PTH receptor; Proteasome inhibition