title: Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1.
abstract: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, characterized by aberrant expression of growth-regulating and oncogenic effectors and requiring novel anticancer strategies. The nuclear transporter exportin-1 (XPO1) is highly expressed in MCL and is associated with its pathogenesis. mTOR signaling, a central regulator of cell metabolism, is frequently activated in MCL and is also an important therapeutic target in this cancer. This study investigated the antitumor effects and molecular/metabolic changes induced by the combination of the small-molecule selective inhibitor XPO1 inhibitor KPT-185 and the dual mTORC1/2 kinase inhibitor AZD-2014 on MCL cells. AZD-2014 enhanced the KPT-185-induced inhibition of cell growth and repression of cell viability. The combination of KPT-185 and AZD-2014 downregulated c-Myc and heat shock factor 1 (HSF1) with its target heat shock protein 70 (HSP70). As a consequence, the combination caused repression of ribosomal biogenesis demonstrated by iTRAQ proteomic analyses. Metabolite assay by CETOF-MS showed that AZD-2014 enhanced the KPT-185-induced repression of MCL cellular energy metabolism through the TCA (Krebs) cycle, and further repressed KPT-185-caused upregulation of glycolysis.Thus the simultaneous inhibition of XPO1 and mTOR signaling is a novel and promising strategy targeting prosurvival metabolism in MCL.
authors.affiliation: Department of Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.|Leading Center for the Development and Research of Cancer Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Sekihara
authors.affiliation: Department of Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Saitoh
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Han
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ciurea
authors.affiliation: Department of Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.|Leading Center for the Development and Research of Cancer Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Kikkawa
authors.affiliation: Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Saiko
authors.initials: S
authors.lastname: Kazuno
authors.affiliation: Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hikari
authors.initials: H
authors.lastname: Taka
authors.affiliation: Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kaga
authors.affiliation: Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Arai
authors.affiliation: Department of Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miida
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Department of Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.|Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Department of Next Genertion Hematology Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tabe
mesh_terms: D000179:Acrylates / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology*; D020543:Proteome / Q000187:drug effects*; D040901:Proteomics; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology*; D000097606:Exportin 1 Protein
chemical_list: D000179:Acrylates; D001549:Benzamides; D028884:Karyopherins; D009025:Morpholines; D020543:Proteome; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D058570:TOR Serine-Threonine Kinases; D014230:Triazoles; D000097606:Exportin 1 Protein; C576639:KPT-185; C585537:vistusertib; C546842:MTOR protein, human
keywords: XPO1; mTORC1/2; mantle cell lymphoma; metabolism; selective inhibitor of nuclear export