TY - JOUR
T1 - Selective inhibition of STAT3 induces apoptosis and G1 cell cycle arrest in ALK-positive anaplastic large cell lymphoma
AU - Amin, Hesham M.
AU - McDonnell, Timothy J.
AU - Ma, Yupo
AU - Lin, Quan
AU - Fujio, Yasushi
AU - Kunisada, Keita
AU - Leventaki, Vasiliki
AU - Das, Pamela
AU - Rassidakis, George Z.
AU - Cutler, Cathy
AU - Medeiros, L. Jeffrey
AU - Lai, Raymond
PY - 2004/7/15
Y1 - 2004/7/15
N2 - Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is an aberrant fusion gene product expressed in a subset of cases of anaplastic large cell lymphoma (ALCL). It has been shown that NPM-ALK binds to and activates signal transducer and activator of transcription 3 (STAT3) in vitro, and that STAT3 is constitutively active in ALK+ ALCL cell lines and tumors. In view of the oncogenic potential of STAT3, we further examined its biological significance in ALCL using two ALK+ ALCL cell lines (Karpas 299 and SU-DHL-1) and an adenoviral vector that carries dominant-negative STAT3 (AdSTAT3DN). Infection by AdSTAT3DN led to the expression of STAT3DN in both ALK+ ALCL cell lines at a similar efficiency. Subcellular fractionation studies showed that a significant proportion of the expressed STAT3DN protein translocated to the nucleus, despite the fact that STAT3DN has a mutation at residue 705tyrosine-phenylalanine, a site that is believed to be crucial for STAT3 activation and nuclear translocation. Introduction of STAT3DN induced apoptosis and G1 cell cycle arrest. Western blot studies showed that expression of STAT3DN resulted in caspase-3 cleavage, down-regulation of Bcl-2, Bcl-xL, cyclin D3, survivin, Mcl-1, c-Myc and suppressor of cytokine signaling 3. These results support the concept that STAT3 activation is pathogenetically important in ALCL cells by deregulating the expression of multiple target proteins that are involved in the control of apoptosis and cell cycle progression.
AB - Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is an aberrant fusion gene product expressed in a subset of cases of anaplastic large cell lymphoma (ALCL). It has been shown that NPM-ALK binds to and activates signal transducer and activator of transcription 3 (STAT3) in vitro, and that STAT3 is constitutively active in ALK+ ALCL cell lines and tumors. In view of the oncogenic potential of STAT3, we further examined its biological significance in ALCL using two ALK+ ALCL cell lines (Karpas 299 and SU-DHL-1) and an adenoviral vector that carries dominant-negative STAT3 (AdSTAT3DN). Infection by AdSTAT3DN led to the expression of STAT3DN in both ALK+ ALCL cell lines at a similar efficiency. Subcellular fractionation studies showed that a significant proportion of the expressed STAT3DN protein translocated to the nucleus, despite the fact that STAT3DN has a mutation at residue 705tyrosine-phenylalanine, a site that is believed to be crucial for STAT3 activation and nuclear translocation. Introduction of STAT3DN induced apoptosis and G1 cell cycle arrest. Western blot studies showed that expression of STAT3DN resulted in caspase-3 cleavage, down-regulation of Bcl-2, Bcl-xL, cyclin D3, survivin, Mcl-1, c-Myc and suppressor of cytokine signaling 3. These results support the concept that STAT3 activation is pathogenetically important in ALCL cells by deregulating the expression of multiple target proteins that are involved in the control of apoptosis and cell cycle progression.
KW - Adenoviral vectors
KW - Anaplastic large cell lymphoma
KW - Apoptosis
KW - Cell cycle
KW - NPM-ALK
KW - STAT3
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U2 - 10.1038/sj.onc.1207703
DO - 10.1038/sj.onc.1207703
M3 - Article
C2 - 15184887
AN - SCOPUS:3843062504
SN - 0950-9232
VL - 23
SP - 5426
EP - 5434
JO - Oncogene
JF - Oncogene
IS - 32
ER -