title: Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling.
abstract: Persistently activated JAK/STAT3 signaling pathway plays a pivotal role in various human cancers including major carcinomas and hematologic tumors, and is implicated in cancer cell survival and proliferation. Therefore, inhibition of JAK/STAT3 signaling may be a clinical application in cancer therapy. Here, we report that 2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo [1,3]oxathiol-4-one (BOT-4-one), a small molecule inhibitor of JAK/STAT3 signaling, induces apoptosis through inhibition of STAT3 activation. BOT-4-one suppressed cytokine (upd)-induced tyrosine phosphorylation and transcriptional activity of STAT92E, the sole Drosophila STAT homolog. Consequently, BOT-4-one significantly inhibited STAT3 tyrosine phosphorylation and expression of STAT3 downstream target gene SOCS3 in various human cancer cell lines, and its effect was more potent in JAK3-activated Hodgkin's lymphoma cell line than in JAK2-activated breast cancer and prostate cancer cell lines. In addition, BOT-4-one-treated Hodgkin's lymphoma cells showed decreased cell survival and proliferation by inducing apoptosis through down-regulation of STAT3 downstream target anti-apoptotic gene expression. These results suggest that BOT-4-one is a novel small molecule inhibitor of JAK3/STAT3 signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK3/STAT3 signaling, specifically Hodgkin's lymphoma.
authors.affiliation: Laboratory of Dermato-Immunology Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul.
authors.forename: Byung Hak
authors.initials: BH
authors.lastname: Kim
authors.forename: Yun Sook
authors.initials: YS
authors.lastname: Min
authors.forename: Jung Sook
authors.initials: JS
authors.lastname: Choi
authors.forename: Gyeong Hun
authors.initials: GH
authors.lastname: Baeg
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Kim
authors.forename: Jong Wook
authors.initials: JW
authors.lastname: Shin
authors.forename: Tae Yoon
authors.initials: TY
authors.lastname: Kim
authors.forename: Sang Kyu
authors.initials: SK
authors.lastname: Ye
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004330:Drosophila / Q000201:enzymology / Q000378:metabolism; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008223:Lymphoma / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C561472:2-cyclohexylimino-6-methyl-6,7-dihydro-5H-benzo(1,3)oxathiol-4-one; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D029721:Drosophila Proteins; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; C105675:Stat92E protein, Drosophila; D053616:Janus Kinase 3