Glycolytic enzyme hexokinase II is a putative therapeutic target in B-cell malignant lymphoma
Glycolytic enzyme hexokinase II is a putative therapeutic target in B-cell malignant lymphoma
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DOI：
10.1016/j.exphem.2019.09.023
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发表时间：
2019-10-01
影响因子：
2.6
通讯作者：
Kirito, Keita
中科院分区：
文献类型：
--
作者：
Nakajima, Kei;Kawashima, Ichiro;Kirito, Keita
己糖激酶II（HXKII）是葡萄糖代谢的关键调节剂，其将葡萄糖转化为葡萄糖6-磷酸。此外，HXKII通过抑制细胞色素c的释放来阻断细胞凋亡。HXKII过表达经常在几种类型的癌症中观察到，并赋予癌细胞化学抗性。在本研究中，我们发现，与弥漫性大B细胞淋巴瘤（DLBCL）患者产生的细胞系相比，具有伯基特淋巴瘤特征的细胞系由于c-MYC和HIF-1的激活而具有更高水平的HXKH。在常氧下，HXKII水平与每个B细胞淋巴瘤细胞系的生长能力相关。当B细胞淋巴瘤细胞在缺氧条件下培养时，HXKII水平进一步增强。低氧诱导的高水平HXKII在所有测试的B细胞淋巴瘤细胞系中赋予顺铂抗性。HDAC抑制剂帕比司他在常氧和缺氧条件下均显著抑制HXKII表达。重要的是，帕比司他逆转了顺铂的抗淋巴瘤作用，并且这种作用被缺氧减弱。这些数据表明，HXKII发挥不同的作用，包括在糖酵解的调节和细胞凋亡的抑制，这取决于其表达水平。此外，通过帕比司他抑制HXKII表达可能代表克服顺铂耐药性的新的和有吸引力的策略。(C)2019 ISEH -血液学和干细胞学会。爱思唯尔公司出版All rights reserved.
Hexokinase II (HXKII) is a key regulator of glucose metabolism that converts glucose to glucose 6-phosphate. Furthermore, HXKII blocks mitochondria-dependent apoptosis by inhibiting the release of cytochrome c. HXKII overexpression is frequently observed in several types of cancer and confers chemoresistance to cancer cells. In the present study, we found that compared with cell lines generated from diffuse large-B-cell lymphoma (DLBCL) patients, cell lines with features of Burkitt lymphoma have higher levels of HXKH because of the activation of both c-MYC and HIF-1. Under normoxia, HXKII levels were correlated with the growth ability of each B-cell lymphoma cell line. HXKII levels were further enhanced when the B-cell lymphoma cells were cultured under hypoxia. The high levels of HXKII induced by hypoxia conferred cisplatin resistance in all tested B-cell lymphoma cell lines. The HDAC inhibitor panobinostat significantly suppressed HXKII expression under both normoxic and hypoxic conditions. Importantly, panobinostat reversed the anti-lymphoma action of cisplatin, and this effect was diminished by hypoxia. These data suggest that HXKII plays different roles, including in the regulation of glycolysis and inhibition of apoptosis, depending on its expression levels. Furthermore, inhibition of HXKII expression by panobinostat may represent a new and attractive strategy to overcome cisplatin resistance. (C) 2019 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.