Downregulating vaccinia-related kinase 1 by luteolin suppresses ovarian cancer cell proliferation by activating the p53 signaling pathway
Downregulating vaccinia-related kinase 1 by luteolin suppresses ovarian cancer cell proliferation by activating the p53 signaling pathway
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DOI：
10.1016/j.ygyno.2023.04.003
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发表时间：
2023-04-17
影响因子：
4.7
通讯作者：
Kajiyama，Hiroaki
中科院分区：
文献类型：
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作者：
Chang，Xuboya;Tamauchi，Satoshi;Kajiyama，Hiroaki
卵巢癌是癌症相关死亡的最常见原因之一，预防卵巢癌患者的化疗耐药和复发仍然是一个挑战。在此，我们的目的是确定的作用，毛地黄黄酮，一种新的治疗剂靶向牛痘相关激酶1（VRK 1），对高级别浆液性卵巢癌（HGSOC）。MethodsPhosphokinase阵列，RNA测序，细胞周期和凋亡测定进行，以确定毛地黄黄酮对HGSOC细胞的影响的潜在机制。通过多种方法评估口服和腹腔注射木犀草素对患者来源的异种移植瘤模型的抗癌作用，包括评估肿瘤大小和磷酸化p53、磷酸化组蛋白H3和切割的caspase 3的免疫组化。结果木犀草素降低HGSOC细胞增殖，增加细胞凋亡和细胞周期停滞在G2/M。与对照组相比，几个基因在木犀草素处理的细胞失调，木犀草素激活p53信号通路。人磷酸激酶阵列显示不同的p53上调木犀草素处理的细胞，证实p53磷酸化在ser 15和ser 46使用蛋白质印迹分析。在患者来源的异种移植模型中，口服或腹膜内给药毛地黄黄酮基本上抑制了肿瘤生长。此外，联合治疗涉及木犀草素和顺铂抑制肿瘤细胞增殖，特别是在顺铂耐药HGSOC细胞line.ConclusionsLuteolin表现出相当大的抗癌作用对HGSOC细胞，减少VRK 1的表达，并激活p53信号通路，从而诱导细胞凋亡和细胞周期阻滞在G2/M期，抑制细胞增殖。此外，木犀草素表现出协同作用，顺铂在体内和体外。因此，毛地黄黄酮可以被认为是一个有前途的联合治疗选择HGSOC。
ObjectivesOvarian cancer constitutes one of the most common causes of cancer-related deaths, and preventing chemotherapy resistance and recurrence in patients with ovarian cancer remains a challenge. Herein, we aimed to identify the effect of luteolin, a novel therapeutic agent targeting vaccinia-related kinase 1 (VRK1), on high-grade serous ovarian cancer (HGSOC).MethodsPhosphokinase array, RNA sequencing, and cell cycle and apoptosis assays were conducted to determine the underlying mechanism of the effect of luteolin on HGSOC cells. The anticancer effects of oral and intraperitoneal luteolin administration were assessed in patient-derived xenograft models via several methods, including the assessment of tumor size and immunohistochemistry of phospho-p53, phosphor-HistoneH3 and cleaved caspase 3.ResultsLuteolin reduced HGSOC cell proliferation and increased apoptosis and cell cycle arrest at G2/M. Compared with controls, several genes were dysregulated in luteolin-treated cells, and luteolin activated the p53 signaling pathway. The human phosphokinase array revealed distinct p53 upregulation in luteolin-treated cells, as confirmed by p53 phosphorylation at ser15 and ser46 using western blot analysis. In patient-derived xenograft models, oral or intraperitoneal luteolin administration substantially suppressed tumor growth. Moreover, combination treatment involving luteolin and cisplatin inhibited tumor cell proliferation, especially in cisplatin-resistant HGSOC cell lines.ConclusionsLuteolin demonstrated considerable anticancer effect on HGSOC cells, reduced VRK1 expression, and activated the p53 signaling pathway, thereby inducing apoptosis and cell cycle arrest in G2/M and inhibiting cell proliferation. Furthermore, luteolin exhibited a synergistic effect with cisplatin both in vivo and in vitro. Thus, luteolin can be considered a promising cotreatment option for HGSOC.