Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3.
Aberrant expression of the ALK tyrosine kinase as a chimeric protein with nucleophosmin (NPM) and other partners plays a key role in malignant cell transformation of T-lymphocytes and other cells. Here we report that two small-molecule, structurally related, quinazoline-type compounds, WHI-131 and WHI-154, directly inhibit enzymatic activity of NPM/ALK as demonstrated by in vitro kinase assays using a synthetic tyrosine-rich oligopeptide and the kinase itself as the substrates. The inhibition of NPM/ALK activity resulted in malignant T cells in suppression of their growth, induction of apoptosis and inhibition of tyrosine phosphorylation of STAT3, the key effector of the NPM/ALK-induced oncogenesis. We also show that the STAT3 tyrosine phosphorylation is mediated in the malignant T cells by NPM/ALK independently of Jak3 kinase as evidenced by the presence of STAT3 phosphorylation in the NPM/ALK-transfected BaF3 cells that do not express detectable Jak3 and in the NPM/ALK-positive malignant T cells with either Jak3 activity impaired by a pan-Jak or Jak3-selective inhibitor or Jak3 expression abrogated by Jak3 siRNA. The above results represent the 'proof-of-principle' experiments with regard to the ALK enzymatic activity as an attractive therapeutic target in T-cell lymphomas and other malignancies that express the kinase in an active form.
Marzec
Michal
M
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Kasprzycka
Monika
M
Ptasznik
Andrzej
A
Wlodarski
Pawel
P
Zhang
Qian
Q
Odum
Niels
N
Wasik
Mariusz A
MA
D000077548:Anaplastic Lymphoma Kinase; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D053616:Janus Kinase 3; D016399:Lymphoma, T-Cell / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases; D050796:STAT3 Transcription Factor / Q000378:metabolism*
D004791:Enzyme Inhibitors; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C116180:WHI P131; C113888:WHI P154; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3