Kim Byung Hak, Yin Chang-Hong, Guo Qianxu, Bach Erika A, Lee Haeryun, Sandoval Claudio, Jayabose Somasundaram, Ulaczyk-Lesanko Agnieszka, Hall Dennis G, Baeg Gyeong-Hun
Department of Pediatrics, Division of Hematology/Oncology, New York Medical College, Valhalla, NY 10595, USA.
Mol Cancer Ther. 2008 Sep;7(9):2672-80. doi: 10.1158/1535-7163.MCT-08-0309.
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.
JAK/STAT信号通路的异常激活在人类癌症中频繁发生，且与癌细胞的存活和增殖相关。因此，开发STAT信号通路的药理学抑制剂在人类癌症治疗中具有潜在的治疗价值。在此，我们报告了2-[(3,5-双三氟甲基苯基)-羟甲基]-1-(4-硝基苯基氨基)-6-苯基-1,2,4a,7a-四氢-吡咯并[3,4-b] -吡啶-5,7-二酮（AUH-6-96），它是一种新型的JAK/STAT信号通路小分子抑制剂，我们最初通过使用培养的果蝇细胞进行基于细胞的高通量筛选鉴定得到。用AUH-6-96处理果蝇细胞导致未配对诱导的转录活性降低以及STAT92E（果蝇唯一的STAT同源物）的酪氨酸磷酸化减少。在人类癌细胞系中，AUH-6-96抑制组成型和白细胞介素-6诱导的STAT3磷酸化。具体而言，在霍奇金淋巴瘤L5细胞中，用AUH-6-96处理导致酪氨酸磷酸化的STAT3水平以及STAT3下游靶基因SOCS3的水平呈剂量和时间依赖性降低。此外，经AUH-6-96处理的L540细胞显示持续激活的JAK3表达降低，这表明AUH-6-96通过影响JAK3活性并随后阻断STAT3信号传导来抑制L540细胞中的JAK/STAT途径信号传导。重要的是，AUH-6-96仅选择性地影响具有异常JAK/STAT信号传导的癌细胞的细胞活力。为支持AUH-6-96对JAK/STAT信号传导抑制的特异性，用AUH-6-96处理通过下调STAT3下游靶标抗凋亡基因（如Bcl-xL）的表达诱导程序性细胞死亡，从而降低癌细胞存活率。总之，本研究表明AUH-6-96是一种新型的JAK/STAT信号通路小分子抑制剂，在治疗具有异常JAK/STAT信号传导的人类癌症中可能具有治疗潜力。
