Isoxazolyl-relea衍生物通过废除结肠癌细胞中的Wnt/β-catenin轴唤起凋亡和副作用
Isoxazolyl-urea derivative evokes apoptosis and paraptosis by abrogating the Wnt/β-catenin axis in colon cancer cells
影响因子:5.40000
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
摘要
在包括结肠癌在内的许多类型的人类恶性肿瘤中，观察到Wnt/β-catenin途径的失调激活。 Wnt/β-catenin途径的废除已被证明是诱导癌细胞死亡的一种有效方法。在此，合成了一种新的异恶唑基-REEA（QR-5），并检查了其对结肠癌细胞系的生存能力的功效。 QR-5在正常对应物上显示出对结肠癌细胞的选择性细胞毒性。 QR-5诱导的凋亡是由亚G1细胞升高所证明的，Bcl-2，MMP-9，COX-2，VEGF和PARP和CASPASE-3的切割降低。 QR-5降低了线粒体膜电位，降低了ALIX的表达，并升高了ATF4的表达和CHOP，表明促进症的诱导。细胞凋亡的抑制剂（Z-DEVD-FMK）和propaptosis（CHX）无法恢复QR-5处理的细胞中的ALIX表达和PARP裂解，从而分别表明两种细胞死亡途径之间的互补。 QR-5抑制了Wnt/β-catenin途径蛋白的表达，这也通过核和细胞质β-catenin的下调证明了这一点。使用β-catenin特异性siRNA的敲低实验证明了QR-5对β-catenin对诱导细胞凋亡和paraptosis的依赖性。总体而言，QR-5通过减轻结肠癌细胞中的Wnt/β-catenin轴来诱导凋亡和popaptosis。
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.