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

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.