Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 89, Issue 4, Pages 824-836Publisher
WILEY-LISS
DOI: 10.1002/jcb.10557
Keywords
IL-2 receptors; cell cycle; apoptosis; Bcl-2; Bcl-X-L; proteasome; Jak3
Categories
Funding
- NCI NIH HHS [R01 CA-63513] Funding Source: Medline
- NIDCR NIH HHS [P01 DE-12321] Funding Source: Medline
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It has been previously demonstrated that human carcinomas express interleukin-2 receptor (IL-2R) a, P, and gamma chains. The beta and gamma chains of IL-2Ralpha 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, PCl-13, which was genetically engineered to overexpress the IL-2Ralpha chain. While IL-2Ralpha-overexpressing PCl-13 cells were capable of forming colonies in soft agar, PCl-13 cells transfected with the control vector or those expressing IL-2 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, BCI-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. (C) 2003 Wiley-Liss, Inc.
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