Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1.
Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1.
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DOI：
10.18632/oncotarget.16602
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发表时间：
2017-05-23
期刊：
影响因子：
--
通讯作者：
Tabe Y
中科院分区：
文献类型：
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作者：
Sekihara K;Saitoh K;Han L;Ciurea S;Yamamoto S;Kikkawa M;Kazuno S;Taka H;Kaga N;Arai H;Miida T;Andreeff M;Konopleva M;Tabe Y
套细胞淋巴瘤(MCL)是一种侵袭性B细胞淋巴瘤，预后差，以生长调节因子和致癌效应因子的异常表达为特征，需要新的抗癌策略。核转运蛋白Exportin-1(XPO1)在MCL中高表达，并与其发病机制有关。MTOR信号是细胞代谢的中心调节器，在MCL中经常被激活，也是MCL的重要治疗靶点。本研究探讨了小分子选择性抑制剂XPO1抑制剂KPT-185和双重mTORC1/2激酶抑制剂AZD-2014联合应用对MCL细胞的抗肿瘤作用及其分子代谢变化。AZD-2014增强了KPT-185对细胞生长的抑制和对细胞活力的抑制。联合应用KPT-185和AZD-2014可下调c-Myc和热休克因子1(HSF1)及其靶标热休克蛋白70(HSP70)的表达。结果，iTRAQ蛋白质组分析表明，这种结合导致了核糖体生物发生的抑制。代谢产物的CETOF-MS分析表明，AZD-2014通过TCA(Krebs)循环增强了KPT-185对MCL细胞能量代谢的抑制，并进一步抑制了KPT-185引起的糖酵解上调。因此，同时抑制XPO1和mTOR信号是一种针对MCL生存代谢的新的、有前景的策略。
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.