Rocaglamide reprograms glucose metabolism in erythroleukemic cells via c-MYC transcriptional regulation of TXNIP and HK2

IF 4.8 2区 医学 Q1 CHEMISTRY, MEDICINAL
Jialei Song , Wuling Liu , Xiao Xiao , Jingrui Song , Chunlin Wang , Babu Gajendran , Xuenai Wei , Changfu Yang , Yunzhi Chen , Yiying Yang , Lei Huang , Junrong Song , Yaacov Ben-David , Yanmei Li
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引用次数: 0

Abstract

Ethnopharmacological relevance

The theory of traditional Chinese medicine (TCM) views leukemia as an imbalance between cell growth and death mainly caused by blood stasis. Medicinal plants Aglaia Lour. (family Meliaceae) are traditionally used as folk medicine in China. It possesses the effects of removing blood stasis and swelling for treatment of cancer. Rocaglamide (RocA) is the main active phytochemical component of the genus Aglaia Lour. Possessing highly anti-leukemia properties. However, the molecular mechanisms by which RocA exerts its anti-growth effect on erythroleukemia cells are largely unknown.

Aim of the study

This study aimed to explore the underlying mechanism and glucose metabolism regulation effects of RocA responsible for its anti-erythroleukemia activity.

Materials and methods

Human erythroleukemic cells were tested for glucose metabolism and treated with glucose deprivation and RocA. MTT assay, cell cycle and apoptosis were used to elucidate growth inhibition. Glucose uptake, glucose consumption and lactate production were evaluated for identification of glucose metabolism. Luciferase assay and ChIP were used to examine the transcriptional activity of c-MYC on the conserved E-boxes binding of the TXNIP (thioredoxin-interacting protein) and HK2 (hexokinase 2) genes. siRNA, shRNA and exogenous transfection were employed to elucidate the effects of TXNIP and HK2 on glucose metabolism.

Results

We find that glucose deprivation results in growth inhibition, cell cycle arrest and extensive apoptosis in erythroleukemic cells accompanied by downregulation of c-MYC and HK2, responsible for glucose metabolism. The similar results emerged in RocA treated erythroleukemic cells in presence of glucose. RocA is shown to decrease glucose uptake, glucose consumption and lactate production. Mechanistically, RocA dramatically increases TXNIP expression through interference with c-MYC binding to the promoter of the TXNIP gene. RocA also represses c-MYC transcriptional recognition of conserved E-boxes in the HK2 first intron, resulting in HK2 loss. These results implicate c-MYC as an important regulator of TXNIP and HK2 after RocA treatment. TXNIP overexpression or knockdown of HK2 suppresses the proliferation of erythroleukemic cells. Ectopic TXNIP expression restricts glucose uptake and HK2 suppression decreases glucose utilization. Further, our data suggests that loss of HK2 weakens the RocA-driven inhibition effects. We propose repression of c-MYC or the binding by RocA upregulates TXNIP and downregulates HK2, possibly contributes to growth inhibition in human erythroleukemic cells.

Conclusions

This study uncovers molecular mechanism of RocA against leukemic cells proliferation, linking the anti-erythroleukemia properties of RocA to glucose metabolism.

Abstract Image

Rocaglamide 通过 c-MYC 对 TXNIP 和 HK2 的转录调控,重新规划红细胞白血病细胞的葡萄糖代谢。
民族药理学意义:传统中医理论认为白血病主要是由血瘀引起的细胞生长和死亡之间的失衡。药用植物 Aglaia Lour.(科)是中国传统的民间药材。它具有化瘀消肿的功效,可用于治疗癌症。Rocaglamide (RocA) 是姬松萝属植物的主要活性植物化学成分,具有很强的抗白血病作用。然而,RocA 对红细胞白血病细胞产生抗生长作用的分子机制尚不清楚:研究目的:本研究旨在探索 RocA 抗红细胞白血病活性的内在机制和葡萄糖代谢调节作用。材料和方法:对人红细胞白血病细胞进行葡萄糖代谢测试,并用葡萄糖剥夺和 RocA 处理。MTT 试验、细胞周期和细胞凋亡用于阐明生长抑制作用。葡萄糖摄取、葡萄糖消耗和乳酸盐生成的评估用于鉴定葡萄糖代谢。采用siRNA、shRNA和外源转染来阐明TXNIP和HK2对葡萄糖代谢的影响:结果:我们发现,葡萄糖剥夺会导致红细胞白血病细胞的生长抑制、细胞周期停滞和大量凋亡,并伴随着负责葡萄糖代谢的 c-MYC 和 HK2 基因的下调。在有葡萄糖存在的情况下,经 RocA 处理的红细胞白血病细胞也出现了类似的结果。结果表明,RocA 可减少葡萄糖摄取、葡萄糖消耗和乳酸生成。从机理上讲,RocA 通过干扰 c-MYC 与 TXNIP 基因启动子的结合,显著增加了 TXNIP 的表达。RocA 还能抑制 c-MYC 对 HK2 第一个内含子中保守的 E-boxes 的转录识别,导致 HK2 缺失。这些结果表明,经 RocA 处理后,c-MYC 是 TXNIP 和 HK2 的重要调节因子。过表达 TXNIP 或敲除 HK2 可抑制红细胞白血病细胞的增殖。TXNIP 的异位表达限制了葡萄糖的摄取,而 HK2 的抑制则降低了葡萄糖的利用率。此外,我们的数据表明,HK2 的缺失会削弱 RocA 驱动的抑制作用。我们认为,c-MYC的抑制或RocA的结合上调了TXNIP,下调了HK2,可能是人类红细胞白血病细胞生长抑制的原因:本研究揭示了 RocA 抗白血病细胞增殖的分子机制,将 RocA 的抗红细胞白血病特性与葡萄糖代谢联系起来。
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来源期刊
Journal of ethnopharmacology
Journal of ethnopharmacology 医学-全科医学与补充医学
CiteScore
10.30
自引率
5.60%
发文量
967
审稿时长
77 days
期刊介绍: The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.
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