Downregulating vaccinia-related kinase 1 by luteolin suppresses ovarian cancer cell proliferation by activating the p53 signaling pathway

被引:13
|
作者
Chang, Xuboya [1 ]
Tamauchi, Satoshi [1 ,5 ]
Yoshida, Kosuke [1 ,2 ]
Yoshihara, Masato [1 ]
Yokoi, Akira [1 ,2 ]
Shimizu, Yusuke [1 ,3 ]
Ikeda, Yoshiki [1 ]
Yoshikawa, Nobuhisa [1 ]
Kiyono, Tohru [4 ]
Yamamoto, Yusuke
Kajiyama, Hiroaki [1 ]
机构
[1] Nagoya Univ, Dept Obstet & Gynecol, Grad Sch Med, Nagoya 4668550, Japan
[2] Nagoya Univ, Inst Adv Res, Nagoya 4648601, Japan
[3] Natl Canc Ctr, Lab Integrat Oncol, Tokyo 1040045, Japan
[4] Exploratory Oncol Res & Clin Trial Ctr, Project Prevent HPV related Canc, Chiba 2778577, Japan
[5] Nagoya Grad Sch Med, Dept Obstet & Gynecol, 65 Tsuruma Cho,Showa Ku, Nagoya 4668550, Japan
基金
日本学术振兴会;
关键词
Ovarian cancer; Luteolin; Vaccinia-related kinase; Patient-derived xenograft; Flavonoid; RESISTANCE;
D O I
10.1016/j.ygyno.2023.04.003
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Objectives. Ovarian cancer constitutes one of the most common causes of cancer-related deaths, and prevent-ing 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).Methods. Phosphokinase array, RNA sequencing, and cell cycle and apoptosis assays were conducted to deter-mine the underlying mechanism of the effect of luteolin on HGSOC cells. The anticancer effects of oral and intra-peritoneal 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. Results. Luteolin reduced HGSOC cell proliferation and increased apoptosis and cell cycle arrest at G2/M. Com-pared with controls, several genes were dysregulated in luteolin-treated cells, and luteolin activated the p53 sig-naling 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, com-bination treatment involving luteolin and cisplatin inhibited tumor cell proliferation, especially in cisplatin-resistant HGSOC cell lines.Conclusions. Luteolin 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.(c) 2023 Elsevier Inc. All rights reserved.
引用
收藏
页码:31 / 40
页数:10
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