Uncoupling JAK3 activation induces apoptosis in human lymphoid cancer cells via regulating critical survival pathways

Nagy, Zsuzsanna S.; Ross, Jeremy A.; Rodriguez, Georgialina; Bader, Julia; Dimmock, Jonathan; Kirken, Robert A.

doi:10.1016/j.febslet.2010.02.071

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Volume 584, Issue 8 , Pages 1515-1520, 16 April 2010

Uncoupling JAK3 activation induces apoptosis in human lymphoid cancer cells via regulating critical survival pathways

Edited by Beat Imhof

Zsuzsanna S. Nagy
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
- Corresponding author. Address: University of Texas at El Paso, Department of Biological Sciences, 500 W. University Ave B 4.130, El Paso, TX 79968, USA. Fax: +1 915 747 5808.
Jeremy A. Ross
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
Georgialina Rodriguez
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA
Julia Bader
- Statistical Consulting Laboratory, The University of Texas at El Paso, El Paso, TX, USA
Jonathan Dimmock
- College of Pharmacy and Nutrition, The University of Saskatchewan, Saskatchewan, Canada
Robert A. Kirken
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX, USA

Received 15 January 2010; received in revised form 23 February 2010; accepted 24 February 2010. published online 10 March 2010.

Abstract

In the current work, we report that specific inhibition of Janus tyrosine kinase (JAK3) via NC1153 induces apoptosis of certain leukemia/lymphoma cell lines. Affymetrix microarray profiling following NC1153 treatment unveiled JAK3 dependent survival modulating pathways (p53, TGF-β, TNFR and ER stress) in Kit225 cells. IL-2 responsive NC1153 target genes were regulated in human JAK3 positive, but not in JAK3 negative lymphoid tumor cells. Moreover, primary lymphoma samples revealed that a number of these genes were reciprocally regulated during disease progression and JAK3 inhibition suggesting that downstream targets of JAK3 could be exploited in the development of novel cancer treatment regimes.

Abbreviations: ALCL, anaplastic large-cell lymphoma, B2M, β-2-microglobulin, DLBCL, diffuse large B-cell lymphoma, GAPDH, glyceraldehyde 3-phosphate dehydrogenase, JAK, Janus tyrosine kinase, PARP, poly-(ADP-ribose) polymerase, PY, phosphor-tyrosine, STAT, signal transducer and activator of transcription, TGF, transforming growth factor, TNF, tumor necrosis factor, qRT² PCR, quantitative real time reverse transcriptase polymerase chain reaction, WB, Western blot