Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
China-US (Henan) Hormel Cancer Institute, Zhengzhou, China.
Phytother Res. 2020 Aug;34(8):2032-2043. doi: 10.1002/ptr.6661. Epub 2020 Mar 6.
Esophageal cancer (EC) is one of the leading causes to cancer death in the worldwide and major population of EC is esophageal squamous cell carcinoma (ESCC). Still, ESCC-targeted therapy has not been covered yet. In the present study we have identified that Licochalcone B (Lico B) inhibited the ESCC growth by directly blocking the Janus kinase (JAK) 2 activity and its downstream signaling pathway. Lico B suppressed KYSE450 and KYSE510 ESCC cell growth, arrested cell cycle at G2/M phase and induced apoptosis. Direct target of Lico B was identified by kinase assay and verified with in vitro and ex vivo binding. Computational docking model predicted for Lico B interaction to ATP-binding pocket of JAK2. Furthermore, treatment of JAK2 clinical medicine AZD1480 to ESCC cells showed similar tendency with Lico B. Thus, JAK2 downstream signaling proteins phosphorylation of STAT3 at Y705 and S727 as well as STAT3 target protein Mcl-1 expression was decreased with treatment of Lico B. Our results suggest that Lico B inhibits ESCC cell growth, arrests cell cycle and induces apoptosis, revealing the underlying mechanism involved in JAK2/STAT3 signaling pathways after Lico B treatment. It might provide potential role of Lico B in the treatment of ESCC.
食管癌（EC）是全球癌症死亡的主要原因之一，而食管癌的主要人群是食管鳞状细胞癌（ESCC）。然而，针对 ESCC 的靶向治疗尚未得到覆盖。在本研究中，我们已经发现，甘草查尔酮 B（Lico B）通过直接阻断 Janus 激酶（JAK）2 的活性及其下游信号通路来抑制 ESCC 的生长。Lico B 抑制 KYSE450 和 KYSE510 ESCC 细胞生长，将细胞周期阻滞在 G2/M 期，并诱导细胞凋亡。通过激酶测定鉴定了 Lico B 的直接靶标，并通过体外和体内结合进行了验证。计算对接模型预测了 Lico B 与 JAK2 的 ATP 结合口袋的相互作用。此外，用 JAK2 临床药物 AZD1480 处理 ESCC 细胞也表现出与 Lico B 相似的趋势。因此，Lico B 处理后 JAK2 下游信号蛋白 STAT3 在 Y705 和 S727 处的磷酸化以及 STAT3 靶蛋白 Mcl-1 的表达减少。我们的结果表明，Lico B 抑制 ESCC 细胞生长，阻滞细胞周期并诱导细胞凋亡，揭示了 Lico B 处理后 JAK2/STAT3 信号通路的潜在作用机制。它可能为 Lico B 在 ESCC 治疗中的应用提供潜在的作用。
