A novel ent-kaurane diterpenoid executes antitumor function in colorectal cancer cells by inhibiting Wnt/β-catenin signaling

被引:20
作者
Ye, Qi [1 ]
Yao, Guangmin [1 ]
Zhang, Mengke [1 ]
Guo, Guoli [1 ]
Hu, Yufeng [1 ]
Jiang, Jue [1 ]
Cheng, Ling [1 ]
Shi, Jianguo [2 ]
Li, Hua [1 ]
Zhang, Yonghui [1 ]
Liu, Hudan [1 ]
机构
[1] Huazhong Univ Sci & Technol, Sch Pharm, Hubei Key Lab Nat Med Chem & Resource Evaluat, Wuhan 430030, Hubei, Peoples R China
[2] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Gastrointestinal Surg, Wuhan 430030, Hubei, Peoples R China
关键词
BETA-CATENIN; TRANSCRIPTIONAL ACTIVATION; COLON-CANCER; CARCINOMA; PATHWAY; GROWTH; MYC; MODULATION; EXPRESSION; MUTATIONS;
D O I
10.1093/carcin/bgv003
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Aberrant activation of Wnt signaling pathway is crucial for the onset and progression of human colorectal cancer (CRC). Owing to the persistent dependence on Wnt signaling for growth and survival, inhibition of this pathway is an attractive approach for new therapies. 11 alpha, 12 alpha-epoxyleukamenin E (EPLE) is a novel ent-kaurane diterpenoid that we previously isolated from Salvia cavaleriei, exhibiting antitumor activities in a variety of cancer cells. Herein, we found that whereas sparing normal human colon mucosal epithelial cells, EPLE selectively inhibited the proliferation of CRC cell lines as well as primary tumor cells. Mechanistically, we demonstrated EPLE exerted its function through suppressing Wnt signaling pathway, as evidenced by EPLE-mediated downregulation of Wnt target genes such as c-Myc, Axin2 and Survivin. Consistently, luciferase reporter assays showed that the EPLE directly blocked Wnt/beta-catenin-mediated transcriptional activation. In combination of co-immunoprecipitation and protein structure-based analyses, we determined that the EPLE entered the interface of beta-catenin/TCF4 complexes and blocked their interaction that is required for beta-catenin-mediated transcriptional activation. Moreover, overexpression of beta-catenin alleviated the cytotoxicity of EPLE in CRC cells, supporting Wnt signaling is a major and specific target of EPLE. Combined treatments of EPLE and 5-fluorouracil, the first-line chemotherapy for CRC patients, achieved a synergistic effect. More importantly, EPLE hampered tumor development in a CRC xenograft model. Our data thus establish EPLE as a novel inhibitor of Wnt signaling that holds great promise as a potential candidate for further preclinical evaluation for CRC treatments.
引用
收藏
页码:318 / 326
页数:9
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