Laboratory of Dermato-Immunology Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul.
Exp Mol Med. 2011 May 31;43(5):313-21. doi: 10.3858/emm.2011.43.5.035.
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.
持续激活的 JAK/STAT3 信号通路在包括主要癌和血液肿瘤在内的各种人类癌症中起着关键作用，并与癌细胞的存活和增殖有关。因此，抑制 JAK/STAT3 信号可能是癌症治疗的临床应用。在这里，我们报告 2-环己基亚氨基-6-甲基-6,7-二氢-5H-苯并[1,3]恶噻酚-4-酮（BOT-4-one），一种 JAK/STAT3 信号的小分子抑制剂，通过抑制 STAT3 激活诱导细胞凋亡。BOT-4-one 抑制细胞因子（upd）诱导的 STAT92E 的酪氨酸磷酸化和转录活性，STAT92E 是唯一的果蝇 STAT 同系物。因此，BOT-4-one 显著抑制了各种人类癌细胞系中 STAT3 酪氨酸磷酸化和 STAT3 下游靶基因 SOCS3 的表达，并且在 JAK3 激活的霍奇金淋巴瘤细胞系中的效果比在 JAK2 激活的乳腺癌和前列腺癌细胞系中更为显著。此外，BOT-4-one 处理的霍奇金淋巴瘤细胞通过下调 STAT3 下游靶抗凋亡基因的表达诱导细胞凋亡，从而导致细胞存活和增殖减少。这些结果表明 BOT-4-one 是一种新型的 JAK3/STAT3 信号小分子抑制剂，在治疗具有异常 JAK3/STAT3 信号的人类癌症（特别是霍奇金淋巴瘤）方面可能具有治疗潜力。
