Direct inhibition of interleukin-2 receptor α-mediated signaling pathway induces G1 arrest and apoptosis in human head-and-neck cancer cells

Overexpression of the interleukin-2 receptor (IL-2R) alpha chain in tumor cells is associated with tumor progression and a poor patient prognosis. IL-2R alpha 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 (PCl-13) genetically engineered to overexpress IL-2R,7, 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-2R alpha(+) 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-2R alpha, and determined the effects of IL-2R alpha 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-2R alpha(+) cells, but not in LacZ cells. In addition, daclizumab activates apoptotic death program via Bcl-2 down-regulation preferentially in IL-2R alpha(+) cells. Finally, daclizumab also sensitizes IL-2R alpha(+) cells to other apoptotic Stimuli, although the effect is moderate. These results indicate that daclizumab inhibits the proliferative potential of IL-2R alpha(+) cells via inhibition of cell cycle progression and induction of apoptosis. (c) 2005 Wiley-Liss, Inc.