Department of Radiation Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China.
Kaohsiung J Med Sci. 2020 Sep;36(9):699-704. doi: 10.1002/kjm2.12224. Epub 2020 May 6.
Ellagic acid (EA) has been reported to have antiproliferative and antioxidant properties, but its function in esophageal squamous cell carcinoma (ESCC) has not been investigated yet. In the current study, EA was found have a significant anti-tumor activity in ESCC. In specific, EA inhibited ESCC cell survival in both of a concentration- and time-dependent manner. And our results showed that EA promoted ESCC cell apoptosis, including inducing the cleavages of PARP, and inhibiting the expression of anti-apoptotic proteins. In mechanistic, EA markedly suppressed STAT3-driven luciferase activity, and inhibited both of the endogenous and cytokines-induced STAT3 activation in ESCC cells. Further investigations indicated that EA could significantly upregulate SHP-1 expression, a negative modulator of STAT3 signaling. In contrast, knockdown of SHP-1 could attenuate the effects of EA on inhibiting ESCC cell survival. Moreover, we found that EA could inhibit RNF6 expression, an E3 of SHP-1, and overexpressing RNF6 could also significantly attenuate the effects of EA on inhibiting ESCC cell survival, which further revealed that EA could inhibit STAT3 signaling by modulating RNF6/SHP-1 axis. Our present study indicated that EA could be as a novel STAT3 inhibitor for the treatment of ESCC.
鞣花酸（EA）具有抗增殖和抗氧化特性，但尚未研究其在食管鳞状细胞癌（ESCC）中的作用。在本研究中，发现 EA 在 ESCC 中具有显著的抗肿瘤活性。具体而言，EA 以浓度和时间依赖性方式抑制 ESCC 细胞存活。我们的研究结果表明，EA 促进 ESCC 细胞凋亡，包括诱导 PARP 的裂解，并抑制抗凋亡蛋白的表达。在机制上，EA 显著抑制 STAT3 驱动的荧光素酶活性，并抑制 ESCC 细胞中内源性和细胞因子诱导的 STAT3 激活。进一步的研究表明，EA 可以显著上调 STAT3 信号的负调节剂 SHP-1 的表达。相反，SHP-1 的敲低可以减弱 EA 对抑制 ESCC 细胞存活的作用。此外，我们发现 EA 可以抑制 RNF6 的表达，RNF6 是 SHP-1 的 E3，过表达 RNF6 也可以显著减弱 EA 对抑制 ESCC 细胞存活的作用，这进一步表明 EA 可以通过调节 RNF6/SHP-1 轴抑制 STAT3 信号。本研究表明，EA 可以作为治疗 ESCC 的新型 STAT3 抑制剂。
