Che Xiao-Fang, Zheng Chun-Lei, Owatari Satsuki, Mutoh Masato, Gotanda Takenari, Jeung Hei-Cheul, Furukawa Tatsuhiko, Ikeda Ryuji, Yamamoto Masatatsu, Haraguchi Misako, Arima Naomichi, Akiyama Shin-ichi
Department of Molecular Oncology, Graduate School of Medical & Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan.
Blood. 2006 Jun 15;107(12):4880-7. doi: 10.1182/blood-2005-08-3423. Epub 2006 Feb 23.
Patients with acute- or lymphoma-type adult T-cell leukemia (ATL) have a poor outcome because of the intrinsic drug resistance to chemotherapy. Protection from apoptosis is a common feature involved in multidrug-resistance of ATL. IAP (inhibitor of apoptosis) family proteins inhibit apoptosis induced by a variety of stimuli. In this study, we investigated the expression of IAP family members (survivin, cIAP1, cIAP2, and XIAP) in the primary leukemic cells from patients with ATL. We found that survivin was overexpressed in ATL, especially in acute-type ATL. Sodium arsenite was shown to down-regulate the expression of survivin at both the protein and RNA levels in a time- and dose-dependent manner, thus inhibiting cell growth, inducing apoptosis, and enhancing the caspase-3 activity in ATL cells. Nuclear factor-kappaB (NF-kappaB) enhances the transcriptional activity of survivin. Sodium arsenite suppressed the constitutive NF-kappaB activation by preventing the IkappaB-alpha degradation and the nuclear translocation of NF-kappaB. These findings suggest that survivin is an important antiapoptotic molecule that confers drug resistance on ATL cells. Sodium arsenite was shown to down-regulate the expression of survivin through the NF-kappaB pathway, thus inhibiting cell growth and promoting apoptosis of ATL cells.
急性或淋巴瘤型成人T细胞白血病（ATL）患者由于对化疗存在内在耐药性，预后较差。免受细胞凋亡是ATL多药耐药所涉及的一个共同特征。凋亡抑制蛋白（IAP）家族蛋白可抑制多种刺激诱导的细胞凋亡。在本研究中，我们调查了ATL患者原代白血病细胞中IAP家族成员（生存素、细胞凋亡抑制蛋白1、细胞凋亡抑制蛋白2和X连锁凋亡抑制蛋白）的表达情况。我们发现生存素在ATL中过度表达，尤其是在急性型ATL中。亚砷酸钠被证明能以时间和剂量依赖的方式在蛋白质和RNA水平下调生存素的表达，从而抑制ATL细胞的生长、诱导细胞凋亡并增强caspase-3活性。核因子-κB（NF-κB）可增强生存素的转录活性。亚砷酸钠通过阻止IκB-α降解和NF-κB的核转位来抑制组成型NF-κB激活。这些发现表明生存素是一种重要的抗凋亡分子，赋予ATL细胞耐药性。亚砷酸钠被证明可通过NF-κB途径下调生存素的表达，从而抑制ATL细胞的生长并促进其凋亡。
