Uncoupling JAK3 activation induces apoptosis in human lymphoid cancer cells via regulating critical survival pathways.
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-beta, 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.
Nagy
Zsuzsanna S
ZS
Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA. znagy@utep.edu
Ross
Jeremy A
JA
Rodriguez
Georgialina
G
Bader
Julia
J
Dimmock
Jonathan
J
Kirken
Robert A
RA
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008223:Lymphoma / Q000235:genetics / Q000473:pathology*; D008352:Mannich Bases / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D007376:Interleukin-2; D008352:Mannich Bases; C503557:NC 1153; D050799:STAT5 Transcription Factor; D053616:Janus Kinase 3