Exp Mol Med.
2011 May;43(5):313-321. 10.3858/emm.2011.43.5.035.
Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling
- Affiliations
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- 1Laboratory of Dermato-Immunology, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-701, Korea.
- 2Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Korea. sangkyu@snu.ac.kr
- 3Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
- 4Department of Beauty and Aesthetic Sciences, Gyeongdo Provincial College, Yecheon 757-807, Korea.
- 5Department of Pediatrics, Division of Hematology/Oncology, New York Medical College, New York 10595, USA.
- 6College of Pharmacy, Chungbuk National University, Cheongju 361-763, Korea.
- 7Department of Internal Medicine, Chung Ang University Hospital Seoul 156-756, Korea.
- KMID: 1009971
- DOI: http://doi.org/10.3858/emm.2011.43.5.035
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.
Keyword
MeSH Terms
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Animals
Antineoplastic Agents/chemistry/*pharmacology
Apoptosis/drug effects
Bicyclo Compounds, Heterocyclic/chemistry/*pharmacology
Cell Line
Cell Proliferation/drug effects
Cell Survival/drug effects
Drosophila/enzymology/metabolism
Drosophila Proteins/antagonists & inhibitors/metabolism
Enzyme Activation/*drug effects
Gene Expression Regulation, Neoplastic/*drug effects
Humans
Janus Kinase 3/*antagonists & inhibitors/metabolism
Lymphoma/enzymology/*metabolism
Phosphorylation/drug effects
STAT Transcription Factors/antagonists & inhibitors/metabolism
STAT3 Transcription Factor/*antagonists & inhibitors/metabolism
Signal Transduction/*drug effects
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