Securinine inhibits the tumor growth of human bladder cancer cells by suppressing Wnt/β-catenin signaling pathway and activating p38 and JNK signaling pathways

作者全名：Xie, Liping; Liang, Shiqiong; Jiwa, Habu; Zhang, Lulu; Lu, Qiuping; Wang, Xiaoxuan; Luo, Lijuan; Xia, Haichao; Li, Ziyun; Wang, Jiayu; Luo, Xiaoji; Luo, Jinyong

作者地址：[Xie, Liping; Liang, Shiqiong; Zhang, Lulu; Lu, Qiuping; Wang, Xiaoxuan; Luo, Lijuan; Xia, Haichao; Li, Ziyun; Wang, Jiayu; Luo, Jinyong] Chongqing Med Univ, Sch Lab Med, Key Lab Diagnost Med Designated Chinese Minist Edu, Chongqing 400016, Peoples R China; [Jiwa, Habu; Luo, Xiaoji] Chongqing Med Univ, Dept Orthoped, Affiliated Hosp 1, Chongqing 400042, Peoples R China; [Luo, Jinyong] Chongqing Med Univ, Key Lab Diagnost Med Designated Chinese Minist Edu, 1 Yixueyuan Rd, Chongqing, Peoples R China

通信作者：Luo, JY (通讯作者)，Chongqing Med Univ, Key Lab Diagnost Med Designated Chinese Minist Edu, 1 Yixueyuan Rd, Chongqing, Peoples R China.

来源：BIOCHEMICAL PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001208265700001

JCR分区：Q1

影响因子：5.3

年份：2024

卷号：223

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Bladder cancer; Securinine; Combination chemotherapy; P38; JNK; Wnt/ beta-catenin

摘要：Bladder cancer (BC) is the most common malignant tumor in urinary system. Although chemotherapy is one of the most important adjuvant treatments for BC, drug resistance, non-specific toxicity and severe side effects are the major obstacles to BC chemotherapy. Natural products have always been a leading resource of antitumor drug discovery, with the advantages of excellent effectiveness, low toxicity, multi-targeting potency and easy availability. In this study, we evaluated the potential anti-tumor effect of securinine (SEC), a natural alkaloid from Securinega suffruticosa, on BC cells in vitro and in vivo, and delineated the underlying mechanism. We found that SEC inhibited the proliferation, migration and invasion, induced the apoptosis of BC cells in vitro, and retarded the xenograft tumor growth of BC cell in vivo. Notably, SEC had a promising safety profile because it presented no or low toxicity on normal cells and mice. Mechanistically, SEC inactivated Wnt/beta-catenin signaling pathway while activated p38 and JNK signaling pathway. Moreover, beta-catenin overexpression, the p38 inhibitor SB203580 and the JNK inhibitor SP600125 both mitigated the inhibitory effect of SEC on BC cells. Furthermore, we demonstrated a synergistic inhibitory effect of SEC and gemcitabine (GEM) on BC cells in vitro and in vivo. Taken together, our findings suggest that SEC may exert anti-BC cell effect at least through the activation of p38 and JNK signaling pathways, and the inhibition of Wnt/beta-catenin signaling pathway. More meaningfully, the findings indicate that GEM-induced BC cell killing can be enhanced by combining with SEC.

基金机构：National Natural Science Foundation of China [81874001]; Program for Youth Innovation in Future Medicine of Chongqing Medical University [W0086]

基金资助正文：<B>Funding</B> This work was supported by the National Natural Science Foundation of China (No. 81874001) and the Program for Youth Innovation in Future Medicine of Chongqing Medical University (No. W0086) .