Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2019; 10:6842-6842.

Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1

Kazumasa Sekihara, Kaori Saitoh, Lina Han, Stefan Ciurea, Shinichi Yamamoto, Mika Kikkawa, Saiko Kazuno, Hikari Taka, Naoko Kaga, Hajime Arai, Takashi Miida, Michael Andreeff, Marina Konopleva and Yoko Tabe _

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Oncotarget. 2017; 8:34552-34564. https://doi.org/10.18632/oncotarget.16602

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Abstract

Kazumasa Sekihara1,2, Kaori Saitoh1, Lina Han3, Stefan Ciurea3, Shinichi Yamamoto1,2, Mika Kikkawa4, Saiko Kazuno4, Hikari Taka4, Naoko Kaga4, Hajime Arai4, Takashi Miida1, Michael Andreeff3, Marina Konopleva3, Yoko Tabe1,3,5

1Department of Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

2Leading Center for the Development and Research of Cancer Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

3Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

4Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan

5Department of Next Genertion Hematology Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan

Correspondence to:

Yoko Tabe, email: tabe@juntendo.ac.jp

Keywords: mantle cell lymphoma, mTORC1/2, selective inhibitor of nuclear export, XPO1, metabolism

Received: May 31, 2016     Accepted: March 16, 2017     Published: March 27, 2017

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.


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