Huang Wen-Shih, Kuo Yi-Hung, Kuo Hsing-Chun, Hsieh Meng-Chiao, Huang Cheng-Yi, Lee Ko-Chao, Lee Kam-Fai, Shen Chien-Heng, Tung Shui-Yi, Teng Chih-Chuan
Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
Chang Gung University College of Medicine, Taoyuan, Taiwan.
PLoS One. 2017 Jan 9;12(1):e0168989. doi: 10.1371/journal.pone.0168989. eCollection 2017.
CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone) is a well-known, major active agent of the alkaloid derivative of Camptotheca acuminata with valuable biological properties, including anti-tumorigenic activity. In this study, we investigated the molecular mechanisms by which CIL-102 mediated the induction of cell death, and we performed cell cycle G2/M arrest to clarify molecular changes in colorectal cancer cells (CRC). Treatment of DLD-1 cells with CIL-102 resulted in triggering the extrinsic apoptosis pathway through the activation of Fas-L, caspase-8 and the induction of Bid cleavage and cytochrome c release in a time-dependent manner. In addition, CIL-102 mediated apoptosis and G2/M arrest by phosphorylation of the Jun N-terminus kinase (JNK1/2) signaling pathway. This resulted in the expression of NFκB p50, p300 and CREB-binding protein (CBP) levels, and in the induction of p21 and GADD45 as well as the decreased association of cdc2/cyclin B. Furthermore, treatment with the JNK1/2 (SP600125), NFκB (PDTI) or the p300/CBP (C646) inhibitors abolished CIL-102-induced cell cycle G2/M arrest and reversed the association of cdc2 with cyclin B. Therefore, we demonstrated that there was an increase in the cellular levels of p21 and GADD45 by CIL-102 reduction in cell viability and cell cycle arrest via the activation of the JNK1/2, NFκB p50, p300 and CBP signaling modules. Collectively, our results demonstrated that CIL-102 induced cell cycle arrest and apoptosis of colon cancer cells by upregulating p21 and GADD45 expression and by activating JNK1/2, NFκB p50 and p300 to provide a new mechanism for CIL-102 treatment.
CIL-102（1-[4-(呋喃并[2,3-b]喹啉-4-基氨基)苯基]乙酮）是一种著名的喜树生物碱衍生物的主要活性剂，具有包括抗肿瘤活性在内的宝贵生物学特性。在本研究中，我们研究了CIL-102介导细胞死亡诱导的分子机制，并进行细胞周期G2/M期阻滞以阐明结肠癌细胞（CRC）中的分子变化。用CIL-102处理DLD-1细胞导致通过Fas-L、半胱天冬酶-8的激活以及Bid裂解和细胞色素c释放的诱导以时间依赖性方式触发外源性凋亡途径。此外，CIL-102通过Jun N端激酶（JNK1/2）信号通路的磷酸化介导凋亡和G2/M期阻滞。这导致NFκB p50、p300和CREB结合蛋白（CBP）水平的表达，以及p21和GADD45的诱导以及cdc2/细胞周期蛋白B的结合减少。此外，用JNK1/2（SP600125）、NFκB（PDTI）或p300/CBP（C646）抑制剂处理消除了CIL-102诱导的细胞周期G2/M期阻滞并逆转了cdc2与细胞周期蛋白B的结合。因此，我们证明通过激活JNK1/2、NFκB p50、p300和CBP信号模块，CIL-102降低细胞活力并使细胞周期停滞，从而使细胞内p21和GADD45水平升高。总体而言，我们的结果表明，CIL-102通过上调p21和GADD45表达以及激活JNK1/2、NFκB p50和p300诱导结肠癌细胞的细胞周期停滞和凋亡，为CIL-102治疗提供了新机制。
