Zhu Cuicui, Zhu Qingyi, Wu Zhaomeng, Yin Yingying, Kang Dan, Lu Shan, Liu Ping
Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, China.
Laboratory of Molecular Biology, Jiangsu Province Hospital of TCM, Nanjing, Jiangsu, China.
J Cell Physiol. 2018 Feb;233(2):1104-1119. doi: 10.1002/jcp.25968. Epub 2017 May 24.
Isorhapontigenin (ISO), a naturally phytopolyphenol compound existing in Chinese herb, apples, and various vegetables, has attracted extensive interest in recent years for its diverse pharmacological characteristics. Increasing evidences reveal that ISO can inhibit cancer cell growth by induced apoptosis, however, the molecular mechanisms is not fully understood. In this study, we found for the first time that ISO apparently induced cell growth inhibition and apoptosis by targeting EGFR and its downstream signal pathways in prostate cancer (PCa) cells both in vitro and in vivo, whereas no obviously effect on normal prostate cells. From the results, we found that ISO competitively targeted EGFR with EGF and inhibited EGFR auto-phosphorylation, and then decreased the levels of p-Erk1/2, p-PI3 K, and p-AKT, and further induced down-regulation of p-FOXO1 and promoted FOXO1 nuclear translocation; and finally resulted in a significantly up-regulation of Bim/p21/27/Bax/cleaved Caspase-3/cleaved PARP-1 and a markedly down-regulation of Sp1/Bcl-2/XIAP/Cyclin D1. Moreover, our experimental data demonstrated that treatment of ISO decreased protein level of AR via both inhibiting the expression of AR gene and promoting the ubiquitination/degradation of AR proteins in proteasome. In vivo, we also found that ISO inhibited the growth of subcutaneous xenotransplanted tumor in nude mice by inducing PCa cell growth inhibition and apoptosis. Taken together, all findings here clearly implicated that EGFR-related signal pathways, including EGFR-PI3K-Akt and EGFR-Erk1/2 pathways, were involved in ISO-induced cell growth inhibition and apoptosis in PCa cells, providing a more solid theoretical basis for the application of ISO to treat patients with prostate cancer in clinic.
异丹叶大黄素（ISO）是一种存在于中草药、苹果及多种蔬菜中的天然植物多酚化合物，近年来因其多样的药理特性而备受关注。越来越多的证据表明，ISO可通过诱导凋亡抑制癌细胞生长，然而其分子机制尚未完全明确。在本研究中，我们首次发现，ISO在体外和体内均可通过靶向表皮生长因子受体（EGFR）及其下游信号通路，显著诱导前列腺癌细胞（PCa）生长抑制和凋亡，而对正常前列腺细胞无明显影响。从结果中我们发现，ISO与表皮生长因子（EGF）竞争性靶向EGFR，抑制EGFR自身磷酸化，进而降低磷酸化细胞外信号调节激酶1/2（p-Erk1/2）、磷酸化磷脂酰肌醇-3激酶（p-PI3 K）和磷酸化蛋白激酶B（p-AKT）水平，并进一步诱导磷酸化叉头框蛋白O1（p-FOXO1）下调，促进FOXO1核转位；最终导致Bim/p21/27/Bax/切割的半胱天冬酶-3/切割的聚（ADP-核糖）聚合酶-1（PARP-1）显著上调，以及特异性蛋白1（Sp1）/B细胞淋巴瘤-2（Bcl-2）/X连锁凋亡抑制蛋白（XIAP）/细胞周期蛋白D1显著下调。此外，我们的实验数据表明，ISO处理通过抑制雄激素受体（AR）基因表达以及促进AR蛋白在蛋白酶体中的泛素化/降解，降低了AR蛋白水平。在体内，我们还发现ISO通过诱导PCa细胞生长抑制和凋亡，抑制了裸鼠皮下异种移植瘤的生长。综上所述，所有这些发现清楚地表明，EGFR相关信号通路，包括EGFR-PI3K-Akt和EGFR-Erk1/2通路，参与了ISO诱导的PCa细胞生长抑制和凋亡，为ISO在临床治疗前列腺癌患者中的应用提供了更坚实的理论基础。
