Caudatin potentiates the anti-tumor effects of TRAIL against human breast cancer by upregulating DR5
Caudatin potentiates the anti-tumor effects of TRAIL against human breast cancer by upregulating DR5
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Caudatin 通过上调 DR5 增强 TRAIL 对人类乳腺癌的抗肿瘤作用
DOI：
10.1016/j.phymed.2019.152950
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发表时间：
2019-09-01
期刊：
影响因子：
7.9
通讯作者：
Wang Feng-ze
中科院分区：
文献类型：
--
作者：
Fei Hong-rong;Yuan Chuang;Wang Feng-ze
背景：肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand， TRAIL）在转化细胞中优先诱导凋亡，而大多数正常细胞不受影响的能力已经得到证实。然而，肿瘤对trail诱导的细胞凋亡的内在和获得性耐药性限制了其治疗的适用性。目的：研究从金秋草（Cynanchum auriadatum）根中提取的C-21甾体苷尾蛋白（caudatin）对trail诱导的人乳腺癌细胞凋亡的影响。方法：采用CCK-8法检测细胞生长抑制作用。采用碘化丙啶流式细胞术测定细胞周期分布。TUNEL染色检测细胞凋亡。western blotting检测蛋白表达。结果：尾蛋白增强trail诱导的人乳腺癌细胞凋亡。这种致敏作用是通过上调死亡受体5 （DR5）实现的。DR5的敲除消除了尾蛋白对TRAIL反应的增强作用。尾状蛋白诱导的DR5上调伴随着CHOP表达和p38 MAPK和JNK磷酸化的增加。CHOP敲低阻断尾状蛋白上调的DR5表达。此外，与p38 MAPK和JNK抑制剂共同处理乳腺癌细胞可显著抵消尾状蛋白诱导的DR5表达。结论：我们的研究结果表明，尾蛋白通过激活CHOP、p38 MAPK和jnk介导的DR5表达上调，使乳腺癌细胞对trail诱导的凋亡敏感。TRAIL和尾蛋白的联合治疗可能是一种很有前途的治疗乳腺癌的方法。
Background: The ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to preferentially induce apoptosis in transformed cells while sparing most normal cells is well established. However, the intrinsic and acquired resistance of tumors to TRAIL-induced apoptosis limits its therapeutic applicability.Purpose: We investigated the effect of caudatin, a species of C-21 steroidal glycosides isolated from the roots of Cynanchum auriadatum, on TRAIL-induced apoptosis in human breast cancer cells.Methods: Cell growth inhibition was evaluated by the CCK-8 assay. The cell cycle distribution was assessed by propidium iodide flow cytometry. Apoptosis was determined by TUNEL staining. Protein expression was detected by western blotting analysis.Results: Caudatin enhanced TRAIL-induced apoptosis in human breast cancer cells. This sensitization was achieved by upregulating death receptor 5 (DR5). Knockdown of DR5 abolished the enhancing effect of caudatin on TRAIL responses. The caudatin-induced upregulation of DR5 was accompanied by increased expression of CHOP and phosphorylation of p38 MAPK and JNK. CHOP knockdown blocked caudatin-upregulated DR5 expression. Moreover, cotreatment of breast cancer cells with p38 MAPK and JNK inhibitors significantly counteracted the caudatin-induced expression of DR5.Conclusion: Our results showed that caudatin sensitized breast cancer cells to TRAIL-induced apoptosis through activation of CHOP, p38 MAPK and JNK-mediated upregulation of DR5 expression. The combination of TRAIL and caudatin may be a promising therapeutic approach for the treatment of breast cancer.