Benzoxathiol derivative BOT-4-one suppresses L540 lymphoma cell survival and proliferation via inhibition of JAK3/STAT3 signaling.
10.3858/emm.2011.43.5.035
- Author:
Byung Hak KIM
1
;
Yun Sook MIN
;
Jung Sook CHOI
;
Gyeong Hun BAEG
;
Youngsoo KIM
;
Jong Wook SHIN
;
Tae Yoon KIM
;
Sang Kyu YE
Author Information
1. Laboratory of Dermato-Immunology, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul 137-701, Korea.
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
BOT-4-one;
cancer;
JAK;
small molecule inhibitor, apoptosis;
STAT3
- MeSH:
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
- From:Experimental & Molecular Medicine
2011;43(5):313-321
- CountryRepublic of Korea
- Language:English
-
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.
