Structure, function, and targeting of interleukin 4 receptors on human head and neck cancer cells

Despite advances in diagnosis and treatment, survival rates for patients wi th head and neck cancer have remained unchanged for the last 30 years. in a n attempt to develop novel therapeutic agents, we have observed that a vari ety of murine and human carcinoma cells expresses high levels of receptors for interleukin 4 (IL-4) in vitro and irt vivo. Here, we demonstrate that 1 7 head and neck cancer cell, lines also express surface IL-4 receptors (IL- 4R) and IL-4 binds to IL-4R on one cell line studied with low affinity (k(d ) = 37.9 +/- 0.4 nM). The investigation of the subunit structure of IL-4R d emonstrated that head and neck cancer cell lines expressed mRNA for IL-4R b eta chain (also known as IL-4R alpha) and IL-13R alpha' chain (also known a s IL-13R alpha(1)). However, no cell line expressed IL-2R common gamma-chai n, which is known to be shared with IL-4R in immune cells. IL-4R is functio nal because IL-4 strongly induced activation of signal transducers and acti vators of transcription 6 (STAT-6) in these cell lines. A fusion protein, I L4(38-37)-PE38KDEL, containing translocation and enzymatic domains of Pseud omonas exotoxin and a circularly permuted human IL-4 was found to be highly and specifically cytotoxic to IL-4R-positive head and neck canter cells, a s determined by protein synthesis inhibition assay and confirmed by clonoge nic assay. IL4(38-37)-PE38KDEL induced DNA fragmentation and condensation o f nuclei indicative of apoptotic cell death. These results establish unifor m expression of IL-4R on head and neck cancer cell lines and IL-4 toxin IL4 (38-37)-PE38KDEL as a novel therapeutic agent for the possible treatment of human head and neck cancers.