Overexpression of survivin in primary ATL cells and sodium arsenite induces apoptosis by down-regulating survivin expression in ATL cell lines

• Published in: Blood 2006-06, Vol.107 (12), p.4880-4887
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - drug effects; Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Apoptosis - drug effects; Arsenites - pharmacology; Biological and medical sciences; Cell Nucleus - metabolism; Chemotherapy; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Enzyme Inhibitors - pharmacology; Female; Gene Expression Regulation, Leukemic - drug effects; Hematologic and hematopoietic diseases; Humans; Inhibitor of Apoptosis Proteins; Jurkat Cells; Leukemia-Lymphoma, Adult T-Cell - drug therapy; Leukemia-Lymphoma, Adult T-Cell - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Microtubule-Associated Proteins - biosynthesis; Middle Aged; Neoplasm Proteins - biosynthesis; Pharmacology. Drug treatments; RNA, Neoplasm - metabolism; Sodium Compounds - pharmacology; Survivin; Time Factors; Transcription, Genetic - drug effects
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-08-3423

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-κB (NF-κB) enhances the transcriptional activity of survivin. Sodium arsenite suppressed the constitutive NF-κB activation by preventing the IκB-α degradation and the nuclear translocation of NF-κB. 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-κB pathway, thus inhibiting cell growth and promoting apoptosis of ATL cells.