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.
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.
Kuhn
Deborah J
DJ
Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, College of Medicine, University of South Florida, Tampa, Florida 33612-9497, USA.
Smith
David M
DM
Pross
Seth
S
Whiteside
Theresa L
TL
Dou
Q Ping
QP
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
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