title: A small-molecule compound identified through a cell-based screening inhibits JAK/STAT pathway signaling in human cancer cells.
abstract: Inappropriate activation of JAK/STAT signaling occurs with high frequency in human cancers and is associated with cancer cell survival and proliferation. Therefore, the development of pharmacologic STAT signaling inhibitors has therapeutic potential in the treatment of human cancers. Here, we report 2-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-1-(4-nitro-phenylamino)-6-phenyl-1,2,4a,7a-tetrahydro-pyrrolo[3,4-b]-pyridine-5,7-dione (AUH-6-96) as a novel small-molecule inhibitor of JAK/STAT signaling that we initially identified through a cell-based high-throughput screening using cultured Drosophila cells. Treatment of Drosophila cells with AUH-6-96 resulted in a reduction of Unpaired-induced transcriptional activity and tyrosine phosphorylation of STAT92E, the sole Drosophila STAT homologue. In human cancer cell lines, AUH-6-96 inhibited both constitutive and interleukin-6-induced STAT3 phosphorylation. Specifically, in Hodgkin lymphoma L540 cells, treatment with AUH-6-96 resulted in reduced levels of tyrosine phosphorylated STAT3 and of the STAT3 downstream target gene SOCS3 in a dose- and time-dependent manner. In addition, AUH-6-96-treated L540 cells showed decreased expression of persistently activated JAK3, suggesting that AUH-6-96 inhibits the JAK/STAT pathway signaling in L540 cells by affecting JAK3 activity and subsequently blocking STAT3 signaling. Importantly, AUH-6-96 selectively affected cell viability only of cancer cells harboring aberrant JAK/STAT signaling. In support of the specificity of AUH-6-96 for inhibition of JAK/STAT signaling, treatment with AUH-6-96 decreased cancer cell survival by inducing programmed cell death by down-regulating the expression of STAT3 downstream target antiapoptotic genes, such as Bcl-xL. In summary, this study shows that AUH-6-96 is a novel small-molecule inhibitor of JAK/STAT signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK/STAT signaling.
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Byung Hak
authors.initials: BH
authors.lastname: Kim
authors.forename: Chang-Hong
authors.initials: CH
authors.lastname: Yin
authors.forename: Qianxu
authors.initials: Q
authors.lastname: Guo
authors.forename: Erika A
authors.initials: EA
authors.lastname: Bach
authors.forename: Haeryun
authors.initials: H
authors.lastname: Lee
authors.forename: Claudio
authors.initials: C
authors.lastname: Sandoval
authors.forename: Somasundaram
authors.initials: S
authors.lastname: Jayabose
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Ulaczyk-Lesanko
authors.forename: Dennis G
authors.initials: DG
authors.lastname: Hall
authors.forename: Gyeong-Hun
authors.initials: GH
authors.lastname: Baeg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004330:Drosophila; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D006801:Humans; D007094:Imides / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: C532359:2-((3,5-bis(trifluoromethylphenyl))hydroxymethyl)-2-(4-nitrophenylamino)-6-phenyl-1,2,4a,7a-tetrahydropyrrolo(3,4-b)pyridine-5,7-dione; D000970:Antineoplastic Agents; D007094:Imides; D015850:Interleukin-6; D010880:Piperidines; D050796:STAT3 Transcription Factor; D053616:Janus Kinase 3; D048049:Extracellular Signal-Regulated MAP Kinases
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