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Direct inhibition of interleukin‐2 receptor α‐mediated signaling pathway induces G 1 arrest and apoptosis in human head‐and‐neck cancer cells
Author(s) -
Kuhn Deborah J.,
Dou Q. Ping
Publication year - 2005
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.20446
Subject(s) - apoptosis , cancer research , biology , cell cycle , microbiology and biotechnology , signal transduction , il 2 receptor , jurkat cells , cytokine , t cell , immunology , immune system , biochemistry
Overexpression of the interleukin‐2 receptor (IL‐2R) α chain in tumor cells is associated with tumor progression and a poor patient prognosis. IL‐2Rα is responsible for the high affinity binding of the receptor to IL‐2, leading to activation of several proliferative and anti‐apoptotic intracellular signaling pathways. We have previously shown that human squamous cell carcinoma of a head‐and‐neck line (PCI‐13) genetically engineered to overexpress IL‐2Rα exhibit increased transforming activity, proliferation, and drug resistance, compared to the vector control cells (J Cell Biochem 2003;89:824–836). In this study, we report that IL‐2Rα + cells express high levels of total and phosphorylated Jak3 protein and are more resistant to apoptosis induced by a Jak3 inhibitor than the control LacZ cells. Furthermore, we used daclizumab, a monoclonal antibody specific to IL‐2Rα, and determined the effects of IL‐2Rα inhibition on cell cycle and apoptosis as well as the involvement of potential cell cycle and apoptosis regulatory proteins. We found that daclizumab induces G 1 arrest, associated with down‐regulation of cyclin A protein, preferentially in IL‐2Rα + cells, but not in LacZ cells. In addition, daclizumab activates apoptotic death program via Bcl‐2 down‐regulation preferentially in IL‐2Rα + cells. Finally, daclizumab also sensitizes IL‐2Rα + cells to other apoptotic stimuli, although the effect is moderate. These results indicate that daclizumab inhibits the proliferative potential of IL‐2Rα + cells via inhibition of cell cycle progression and induction of apoptosis. © 2005 Wiley‐Liss, Inc.