Open AccessTargeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1
Author(s) -
Kazumasa Sekihara,
Kaori Saitoh,
Lei Han,
Stefan O. Ciurea,
Shinichi Yamamoto,
Mika Kikkawa,
Saiko Kazuno,
Hikari Taka,
Naoko Kaga,
Hajime Arai,
Takashi Miida,
Michael Andreeff,
Marina Konopleva,
Yoko Tabe
Publication year - 2017
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.16602
Subject(s) - pi3k/akt/mtor pathway , mtorc1 , cancer research , microbiology and biotechnology , mantle cell lymphoma , cell cycle , cell growth , downregulation and upregulation , cell , biology , chemistry , signal transduction , biochemistry , lymphoma , immunology , gene
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.