title: Novel small molecular inhibitors disrupt the JAK/STAT3 and FAK signaling pathways and exhibit a potent antitumor activity in glioma cells.
abstract: JAK (Janus kinase)/STAT (signal transducers and activators of transcription) signaling is involved in the regulation of cell growth, differentiation and apoptosis. Constitutive activation of STATs, in particular STAT3, is observed in a large number of human tumors, including gliomas and may contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis, thus it emerges as a promising target for anti-cancer therapy. To investigate the therapeutic potential of blocking STAT3 in glioma cells a set of small synthetic molecules - caffeic acid derivatives, structurally related to AG490 was screened for its ability to inhibit STAT3. Inhibitor 2 (E)-2-cyano-N-[(S)-1-phenylethyl]-3-(pyridin-2-yl)acrylamide was the most effective in inhibition of JAK/STAT3 signaling and at doses ≥ 25 μM significantly reduced the level of phosphorylated JAK1, JAK2 and STAT3 (at Tyr705) and downregulated the expression of known STAT3 targets. In treated cells we observed rapid detachment and rounding of cells associated with reduction of focal adhesion kinase phosphorylation and activity, followed by upregulation of phosphorylated p38, JNK and ERK1/2 levels. Accumulation of cells with fragmented DNA, increases of the cleaved caspase 3 and fragmented PARP levels were detected 24 h after the treatment suggesting ongoing apoptotic cell death. Three human malignant glioblastoma cell lines defective in tumor suppressors TP53 and/or PTEN were susceptible to inhibitor 2 that induced the programmed cell death. Global gene expression profiling revealed modulation of numerous genes in cells treated with inhibitor 2 revealing novel, potential JAK/STAT targets. Our study demonstrates that suitably modified caffeic acid molecules exhibit significant cytotoxic potential toward glioma cells.
authors.affiliation: Laboratory of Transcription Regulation, The Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Swiatek-Machado
authors.forename: Jakub
authors.initials: J
authors.lastname: Mieczkowski
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Ellert-Miklaszewska
authors.forename: Piotr
authors.initials: P
authors.lastname: Swierk
authors.forename: Izabela
authors.initials: I
authors.lastname: Fokt
authors.forename: Slawomir
authors.initials: S
authors.lastname: Szymanski
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Skora
authors.forename: Wiesław
authors.initials: W
authors.lastname: Szeja
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Grynkiewicz
authors.forename: Bogdan
authors.initials: B
authors.lastname: Lesyng
authors.forename: Waldemar
authors.initials: W
authors.lastname: Priebe
authors.forename: Bozena
authors.initials: B
authors.lastname: Kaminska
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020032:Tyrphostins / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D051416:Focal Adhesion Protein-Tyrosine Kinases; D053612:Janus Kinases; D020928:Mitogen-Activated Protein Kinases