Overexpression of survivin in primary ATL cells and sodium arsenite induces apoptosis by down-regulating survivin expression in ATL cell lines.
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.
Department of Molecular Oncology, Graduate School of Medical & Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima 890-8520, Japan.
Xiao-Fang
XF
Che
Chun-Lei
CL
Zheng
Satsuki
S
Owatari
Masato
M
Mutoh
Takenari
T
Gotanda
Hei-Cheul
HC
Jeung
Tatsuhiko
T
Furukawa
Ryuji
R
Ikeda
Masatatsu
M
Yamamoto
Misako
M
Haraguchi
Naomichi
N
Arima
Shin-ichi
S
Akiyama
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D018053:Arsenites / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D012334:RNA, Neoplasm / Q000378:metabolism; D017670:Sodium Compounds / Q000494:pharmacology*; D000077022:Survivin; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D018053:Arsenites; C107489:BIRC5 protein, human; D004791:Enzyme Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D017670:Sodium Compounds; D000077022:Survivin; C017947:sodium arsenite