Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3

Michal Marzec; Monika Kasprzycka; Andrzej Ptasznik; Pawel Wlodarski; Qian Zhang; Niels Ødum; Mariusz A Wasik

doi:10.1038/labinvest.3700348

Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3

Michal Marzec, Monika Kasprzycka, Andrzej Ptasznik, Pawel Wlodarski, Qian Zhang, Niels Ødum, Mariusz A Wasik

Cellebiologi og Fysiologi

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

62 Citationer (Scopus)

Abstract

Udgivelsesdato: 2005-Dec

Originalsprog	Engelsk
Tidsskrift	Laboratory Investigation
Vol/bind	85
Udgave nummer	12
Sider (fra-til)	1544-54
Antal sider	10
ISSN	0023-6837
DOI	https://doi.org/10.1038/labinvest.3700348
Status	Udgivet - 2005

Bibliografisk note

Keywords: Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Janus Kinase 3; Lymphoma, T-Cell; Phosphorylation; Protein-Tyrosine Kinases; Quinazolines; STAT3 Transcription Factor

Adgang til dokumentet

10.1038/labinvest.3700348

Citationsformater

Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3. / Marzec, Michal; Kasprzycka, Monika; Ptasznik, Andrzej et al.
I: Laboratory Investigation, Bind 85, Nr. 12, 2005, s. 1544-54.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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title = "Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3",

abstract = "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.",

author = "Michal Marzec and Monika Kasprzycka and Andrzej Ptasznik and Pawel Wlodarski and Qian Zhang and Niels {\O}dum and Wasik, {Mariusz A}",

note = "Keywords: Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Janus Kinase 3; Lymphoma, T-Cell; Phosphorylation; Protein-Tyrosine Kinases; Quinazolines; STAT3 Transcription Factor",

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T1 - Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3

AU - Marzec, Michal

AU - Kasprzycka, Monika

AU - Ptasznik, Andrzej

AU - Wlodarski, Pawel

AU - Zhang, Qian

AU - Ødum, Niels

AU - Wasik, Mariusz A

N1 - Keywords: Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Janus Kinase 3; Lymphoma, T-Cell; Phosphorylation; Protein-Tyrosine Kinases; Quinazolines; STAT3 Transcription Factor

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

U2 - 10.1038/labinvest.3700348

DO - 10.1038/labinvest.3700348

M3 - Journal article

C2 - 16170336

SN - 0023-6837

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SP - 1544

EP - 1554

JO - Laboratory Investigation

JF - Laboratory Investigation

IS - 12

ER -