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.
Original language | English (US) |
---|---|
Pages (from-to) | 34552-34564 |
Number of pages | 13 |
Journal | Oncotarget |
Volume | 8 |
Issue number | 21 |
DOIs | |
State | Published - 2017 |
Keywords
- MTORC1/2
- Mantle cell lymphoma
- Metabolism
- Selective inhibitor of nuclear export
- XPO1
ASJC Scopus subject areas
- Oncology