HDAC inhibition induces increased choline uptake and elevated phosphocholine levels in MCF7 breast cancer cells.
HDAC inhibition induces increased choline uptake and elevated phosphocholine levels in MCF7 breast cancer cells.
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DOI：
10.1371/journal.pone.0062610
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Ronen SM
中科院分区：
文献类型：
--
作者：
Ward CS;Eriksson P;Izquierdo-Garcia JL;Brandes AH;Ronen SM
组蛋白去乙酰化酶（HDAC）抑制剂已成为临床上有效的抗肿瘤药物。来自我们实验室和其他人的研究报告称，磁共振波谱（MRS）可检测的磷酸胆碱（PC）在SAHA治疗后升高，提供了一种潜在的非侵入性反应生物标志物。通常，PC升高与癌症相关，而PC降低伴随着对顺铂治疗的反应。因此，本研究的目的是阐明HDAC抑制导致PC升高的潜在生化机制。我们研究了SAHA对MCF-7乳腺癌细胞的影响，使用13 C MRS监测[1，2 - 13 C]胆碱摄取和磷酸化PC。我们发现PC合成在处理的细胞中显著更高，占对照的154±19%。这在31 P MRS检测到的总PC水平增加的标准差范围内（对照的129±7%）。此外，细胞胆碱激酶活性升高（177±31%），而胞苷酰转移酶活性不变。与对照组相比，中等亲和力胆碱转运蛋白SLC 44 A1和胆碱激酶α的表达增加（分别为144%和161%），这一结果通过mRNA微阵列分析和蛋白质水平的Western印迹法确认。综上所述，我们的研究结果表明，在SAHA治疗后PC水平的增加是由于其合成增加。此外，随着治疗的进行，甘油磷酸胆碱（GPC）的浓度显着增加至210± 45%。这可能是由于几种磷脂酶A2（PLA 2）亚型的表达上调，导致SAHA处理的细胞中PLA 2活性增加（162±18%）。重要的是，含总胆碱（tCho）的代谢产物，包括胆碱，PC和GPC的水平，很容易检测临床使用1H MRS。因此，我们的研究结果提供了一个重要的步骤，在验证临床上可翻译的非侵入性成像方法的后续诊断HDAC抑制剂治疗。
Histone deacetylase (HDAC) inhibitors have emerged as effective antineoplastic agents in the clinic. Studies from our lab and others have reported that magnetic resonance spectroscopy (MRS)-detectable phosphocholine (PC) is elevated following SAHA treatment, providing a potential noninvasive biomarker of response. Typically, elevated PC is associated with cancer while a decrease in PC accompanies response to antineoplastic treatment. The goal of this study was therefore to elucidate the underlying biochemical mechanism by which HDAC inhibition leads to elevated PC. We investigated the effect of SAHA on MCF-7 breast cancer cells using 13C MRS to monitor [1,2-13C] choline uptake and phosphorylation to PC. We found that PC synthesis was significantly higher in treated cells, representing 154±19% of control. This was within standard deviation of the increase in total PC levels detected by 31P MRS (129±7% of control). Furthermore, cellular choline kinase activity was elevated (177±31%), while cytidylyltransferase activity was unchanged. Expression of the intermediate-affinity choline transporter SLC44A1 and choline kinase α increased (144% and 161%, respectively) relative to control, as determined by mRNA microarray analysis with protein-level confirmation by Western blotting. Taken together, our findings indicate that the increase in PC levels following SAHA treatment results from its elevated synthesis. Additionally, the concentration of glycerophosphocholine (GPC) increased significantly with treatment to 210±45%. This is likely due to the upregulated expression of several phospholipase A2 (PLA2) isoforms, resulting in increased PLA2 activity (162±18%) in SAHA-treated cells. Importantly, the levels of total choline (tCho)-containing metabolites, comprised of choline, PC and GPC, are readily detectable clinically using 1H MRS. Our findings thus provide an important step in validating clinically translatable non-invasive imaging methods for follow-up diagnostics of HDAC inhibitor treatment.
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