title: Overexpression of interleukin-2 receptor alpha in a human squamous cell carcinoma of the head and neck cell line is associated with increased proliferation, drug resistance, and transforming ability.
abstract: It has been previously demonstrated that human carcinomas express interleukin-2 receptor (IL-2R) alpha, beta, and gamma chains. The beta and gamma chains of IL-2R have intermediate binding affinity for IL-2 and are responsible for the intracellular signaling cascades after IL-2 stimulation. IL-2Ralpha lacks the cytoplasmic domain, but is essential for increasing the IL-2-binding affinity of other receptors. Overexpression of IL-2Ralpha in tumor cells is associated with tumor progression and a poor patient prognosis. To define molecular mechanisms responsible for the effects associated with IL-2Ralpha expression, ex vivo experiments were performed with the squamous cell carcinoma head-and-neck cancer line, PCI-13, which was genetically engineered to overexpress the IL-2Ralpha chain. While IL-2Ralpha-overexpressing PCI-13 cells were capable of forming colonies in soft agar, PCI-13 cells transfected with the control vector or those expressing IL-2Rgamma did not. Consistently, IL-2Ralpha-expressing tumor cells proliferated more rapidly than the control or IL-2Rgamma+ cells, associated with increased levels of cyclins A and D1 and cyclin-dependent kinase (cdk(s)) 2 and 4 proteins. In addition, IL-2Ralpha-expressing cells were significantly more resistant to apoptosis induction by a tripeptidyl proteasome inhibitor (ALLN) and two chemotherapeutic drugs (VP-16 and taxol) than the control or IL-2Rgamma+ cells. Accompanying the drug resistance, high levels of anti-apoptotic Bcl-X(L) and Bcl-2 proteins were found in the mitochondria-containing fraction of IL-2Ralpha-expressing tumor cells. Treatment of IL-2Ralpha-expressing cells with a specific Janus kinase 3 (Jak3) inhibitor decreased expression of cyclin A, cyclin D1, Bcl-X(L), and Bcl-2 proteins. Finally, high levels of ubiquitinated proteins were detected in the proliferating IL-2Ralpha-expressing cells. Our data suggest that increased proliferation rates and decreased drug sensitivity of IL-2Ralpha-expressing tumor cells are responsible for the enhanced tumor aggressiveness and poor clinical prognosis of patients whose tumors express IL-2Ralpha.
authors.affiliation: Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, College of Medicine, University of South Florida, Tampa, Florida 33612-9497, USA.
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Kuhn
authors.forename: David M
authors.initials: DM
authors.lastname: Smith
authors.forename: Seth
authors.initials: S
authors.lastname: Pross
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000502:physiology*; D002461:Cell Line, Transformed; D018844:Cyclin-Dependent Kinases / Q000032:analysis / Q000096:biosynthesis; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003546:Cysteine Endopeptidases / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit; D053616:Janus Kinase 3; D009097:Multienzyme Complexes / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D016213:Cyclins; D004791:Enzyme Inhibitors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D009097:Multienzyme Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; D018123:Receptors, Interleukin; D025801:Ubiquitin; D005047:Etoposide; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D018844:Cyclin-Dependent Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D017239:Paclitaxel