title: JSI-124 (cucurbitacin I) inhibits Janus kinase-3/signal transducer and activator of transcription-3 signalling, downregulates nucleophosmin-anaplastic lymphoma kinase (ALK), and induces apoptosis in ALK-positive anaplastic large cell lymphoma cells.
abstract: JSI-124 (cucurbitacin I) has been recently described as a specific inhibitor of signal transducer and activator of transcription-3 (STAT3). As STAT3 activation is pathogenetically important in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL), we investigated whether JSI-124 can mediate significant inhibitory effects in this cell type. In two ALK+ ALCL cell lines (Karpas 299 and SU-DHL-1), JSI-124 significantly reduced the number of viable cells to 50% of that of negative controls at a dose of 5-10 micromol/l at 24 h and 1-1.25 micromol/l at 48 h. This decrease in viability was associated with apoptosis, as confirmed by the increase in the subG(0/1) fraction, poly(ADP-ribose)polymerase cleavage and expression of active caspase 3. JSI-124 decreased the phosphorylated-STAT3 and -Janus kinase-3 (JAK3) levels in a dose-dependent fashion, and these changes were coupled with significant decreases in several STAT3 downstream targets, including mcl-1, bcl-2, bcl-xL and cyclin D3. Interestingly, JSI-124 also dramatically decreased the protein levels of JAK3 and nucleophosmin (NPM)-ALK, and these effects were reversible by MG132. Our data support that JSI-124 is a potentially useful therapeutic agent for ALK+ ALCL. In addition to its role as a tyrosine kinase inhibitor, JSI-124 appears to be involved in regulating proteosome degradation for proteins such as JAK3 and NPM-ALK.
authors.affiliation: Department of Laboratory Medicine and Pathology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Xinzhe
authors.initials: X
authors.lastname: Shi
authors.forename: Bevin
authors.initials: B
authors.lastname: Franko
authors.forename: Christine
authors.initials: C
authors.lastname: Frantz
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053616:Janus Kinase 3; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D014315:Triterpenes; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3; C038106:cucurbitacin I