Department of Hematology and Rheumatology, Nihon University School of Medicine, Itabashi Hospital, Itabashi-ku, Tokyo 173-8610, Japan.
Oncol Rep. 2013 Jun;29(6):2362-8. doi: 10.3892/or.2013.2388. Epub 2013 Apr 5.
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.
已经有人提出，三氧化二砷（ATO）的细胞毒性作用与水通道蛋白-9（AQP9）的表达水平密切相关，但仍需要详细的研究来证实这种关联。因此，本研究采用两种急性早幼粒细胞白血病（APL）细胞系 NB4 和 HT93A 以及新诊断和复发的 APL 患者的原代 APL 细胞，研究了 AQP9 的表达水平与对 ATO 敏感性之间的相关性。与 HT93A 细胞相比，NB4 细胞对 ATO 介导的凋亡诱导更敏感。此外，通过流式细胞术评估，NB4 细胞中 AQP9 的表达水平明显更高，并且细胞内砷蓄积也更多。更重要的是，与 APL 细胞系相似，AQP9 的表达水平与原代 APL 细胞对 ATO 介导的凋亡诱导的敏感性之间存在密切的相关性。相比之下，在 ATO 敏感性与 AQP9 表达水平相关联方面，并未观察到与细胞表面标志物表达谱和染色体改变之间的相关性。这些结果提供了直接证据，表明 AQP9 的表达水平与 APL 细胞系和原代细胞对 ATO 的敏感性密切相关，而不是与细胞表面标志物和染色体改变等其他生物标志物相关。这些发现表明，AQP9 的表达状态是 APL 患者 ATO 治疗成功的预测标志物，因为 AQP9 在各种亚砷酸盐介导的对正常和癌细胞的生物学效应中发挥关键作用。此外，与目前的方法（如 Western blot）相比，流式细胞术可能是分析 APL 患者 AQP9 状态的一种新的方便且有价值的工具。
