异羟基唑脲衍生物通过破坏Wnt/β-连环蛋白轴在结直肠癌细胞中诱导凋亡和paraptosis
Isoxazolyl-urea derivative evokes apoptosis and paraptosis by abrogating the Wnt/β-catenin axis in colon cancer cells
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影响因子:5.4
分区:医学2区 / 毒理学1区 生化与分子生物学2区 药学2区
发表日期:2024 Aug 25
作者:
Rajaghatta N Suresh, Young Yun Jung, Kachigere B Harsha, Chakrabhavi Dhananjaya Mohan, Kwang Seok Ahn, Kanchugarakoppal S Rangappa
DOI:
10.1016/j.cbi.2024.111143
摘要
在许多类型的人类恶性肿瘤中，包括结直肠癌，观察到Wnt/β-连环蛋白通路的失调激活。已证明破坏Wnt/β-连环蛋白通路是一种有效诱导癌细胞死亡的方法。在本文中，合成了一种新的异羟基唑脲（QR-5），并检测其对结直肠癌细胞系存活率的作用。QR-5对结直肠癌细胞表现出选择性细胞毒性，而对正常细胞则效果较弱。QR-5通过升高亚G1细胞比例、降低Bcl-2、MMP-9、COX-2、VEGF以及引起PARP和Caspase-3裂解，证实其诱导凋亡的作用。QR-5降低线粒体膜电位，降低Alix的表达并升高ATF4和CHOP的表达，提示其诱导paraptosis。凋亡抑制剂（Z-DEVD-FMK）和paraptosis抑制剂（CHX）未能分别恢复QR-5处理细胞中Alix表达和PARP裂解，表明两种细胞死亡途径之间存在互补关系。QR-5抑制Wnt/β-连环蛋白通路蛋白的表达，这通过核和细胞质β-连环蛋白的下调得到证实。β-连环蛋白特异性siRNA敲低实验表明，QR-5依赖β-连环蛋白以诱导凋亡和paraptosis。总之，QR-5通过抑制Wnt/β-连环蛋白轴在结直肠癌细胞中同时诱导凋亡和paraptosis。
Abstract
Deregulated activation of the Wnt/β-catenin pathway is observed in many types of human malignancies including colon cancer. Abrogation of the Wnt/β-catenin pathway has been demonstrated as an effective way of inducing cancer cell death. Herein, a new isoxazolyl-urea (QR-5) was synthesized and examined its efficacy on the viability of colon cancer cell lines. QR-5 displayed selective cytotoxicity towards colon cancer cells over normal counterparts. QR-5 induced apoptosis as evidenced by elevation in sub-G1 cells, decrease in Bcl-2, MMP-9, COX-2, VEGF and cleavage of PARP and caspase-3. QR-5 reduced the mitochondrial membrane potential, decreased the expression of Alix and elevated the expression of ATF4 and CHOP indicating the induction of paraptosis. The inhibitor of apoptosis (Z-DEVD-FMK) and paraptosis (CHX) could not restore Alix expression and PARP cleavage in QR-5 treated cells, respectively suggesting the complementation between the two cell death pathways. QR-5 suppressed the expression of Wnt/β-catenin pathway proteins which was also evidenced by the downregulation of nuclear and cytoplasmic β-catenin. The dependency of QR-5 on β-catenin for inducing apoptosis and paraptosis was demonstrated by knockdown experiments using β-catenin specific siRNA. Overall, QR-5 induces apoptosis as well as paraptosis by mitigating the Wnt/β-catenin axis in colon cancer cells.