Aquaporin 9, a promising predictor for the cytocidal effects of arsenic trioxide in acute promyelocytic leukemia cell lines and primary blasts
Aquaporin 9, a promising predictor for the cytocidal effects of arsenic trioxide in acute promyelocytic leukemia cell lines and primary blasts
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DOI：
10.3892/or.2013.2388
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发表时间：
2013-06-01
期刊：
影响因子：
4.2
通讯作者：
Toyoda, Hiroo
中科院分区：
文献类型：
--
作者：
Iriyama, Noriyoshi;Yuan, Bo;Toyoda, Hiroo
三氧化二砷（ATO）的细胞杀伤作用和水通道蛋白-9（AQP 9）的表达水平之间的密切相关性已被提出，但仍需要详细的研究来证实这种关联。因此，在本研究中，AQP 9的表达水平和ATO的敏感性之间的相关性进行了研究，使用两个急性早幼粒细胞白血病（APL）细胞系，NB 4和HT 93 A，以及原代APL细胞从新诊断的和复发的APL患者。与HT 93 A细胞相比，在NB 4细胞中观察到对ATO介导的凋亡诱导的显著更高的敏感性。此外，使用流式细胞术评估，在NB 4细胞中观察到AQP 9的表达水平显著更高，沿着细胞内砷积累更多。更重要的是，类似于APL细胞系，AQP 9的表达水平的趋势与原代APL细胞对ATO介导的凋亡诱导的差异敏感性密切相关。相反，ATO敏感性与AQP 9表达水平和细胞表面标志物的表达谱以及染色体改变之间没有相关性。这些结果提供了直接的证据表明，AQP 9的表达水平，而不是其他生物标志物，如细胞表面标志物和染色体改变，与ATO在APL细胞系和原代母细胞的敏感性密切相关。这些发现表明，APL患者的AQP 9表达状态是ATO治疗成功的预测标志物，因为AQP 9在亚砷酸盐介导的对正常细胞和癌细胞的各种生物学效应中起着关键作用。此外，流式细胞术可能是一个新的方便和有价值的工具，用于分析APL患者的AQP 9状态相比，目前的方法，如蛋白质印迹。
A close correlation between the cytocidal effects of arsenic trioxide (ATO) and aquaporin-9 (AQP9) expression levels has been proposed, yet detailed studies are still needed to confirm this association. Thus, in the present study, the correlation between the expression levels of AQP9 and sensitivity to ATO was investigated using two acute promyelocytic leukemia (APL) cell lines, NB4 and HT93A, as well as primary APL cells from newly diagnosed and relapsed APL patients. A substantially higher sensitivity to ATO-mediated induction of apoptosis was observed in the NB4 cells when compared to that in the HT93A cells. In addition, markedly higher expression levels of AQP9, as assessed using flow cytometry, along with more intracellular arsenic accumulation, were observed in the NB4 cells. More importantly, similar to APL cell lines, the trend of expression levels of AQP9 correlated closely with the differential sensitivity to ATO-mediated induction of apoptosis in primary APL cells. In contrast, no correlation was observed between ATO sensitivity associated with AQP9 expression levels and the expression profiles of cell surface markers as well as chromosomal alterations. These results provide direct evidence that the expression levels of AQP9, rather than other biomarkers such as cell surface markers and chromosomal alterations, correlate closely with the sensitivity to ATO in both APL cell lines and primary blasts. These findings suggest that the AQP9 expression status of APL patients is a predictive marker for the successful outcome of ATO treatment, since AQP9 plays a pivotal role in various arsenite-mediated biological effects on normal and cancer cells. Moreover, flow cytometry may be a new convenient and valuable tool for analyzing the AQP9 status of APL patients compared to current methods such as western blotting.