Cucielo Maira Smaniotto, Freire Paula Paccielli, Emílio-Silva Maycon Tavares, Romagnoli Graziela Gorete, Carvalho Robson Francisco, Kaneno Ramon, Hiruma-Lima Clélia Akiko, Delella Flávia Karina, Reiter Russel J, Chuffa Luiz Gustavo de Almeida
Department of Structural and Functional Biology, Institute of Biosciences, UNESP - Sao Paulo State University, Botucatu 18618-689 São Paulo, Brazil.
Department of Immunology, Institute of Biomedical Sciences, USP - University of São Paulo, São Paulo, Brazil.
Pathol Res Pract. 2023 Aug;248:154637. doi: 10.1016/j.prp.2023.154637. Epub 2023 Jun 22.
Ovarian cancer is a highly aggressive disease that is frequently diagnosed in advanced stages. Melatonin, with its numerous antitumor properties, holds great promise in cancer treatment. Herein, we investigated the effects of melatonin on apoptosis, cell migration, and kinase levels in human ovarian carcinoma SKOV-3 cells and determined whether these effects are mediated by the activation of the MT1 receptor.
SKOV-3 cells were exposed to different concentrations of melatonin based on the presence of MT1 receptor, and we also performed specific silencing of the melatonin receptor gene MTNR1A.
Our findings revealed that melatonin reduced cell viability as shown by the MTT assay, and flow cytometry analysis showed increased rates of apoptosis and necrosis in all melatonin-treated cells. Melatonin significantly decreased the migratory and invasive capacities of the cells. Propidium iodide labeling indicated that melatonin induced cell cycle arrest by reducing DNA content in the S and G2/M phases in SKOV-3 cells. Additionally, the levels of AKT, ERK1/2, JNK, CREB, p70S6K, STAT3/5, and p38 MAP kinase involved in cell survival, proliferation, motility, and stress responses were depressed by melatonin and further reduced after MT1 knockdown. These molecules were found to be associated with lower overall survival in ovarian cancer patients.
Melatonin had obvious oncostatic actions on ovarian cancer cells, and MT1 receptor knockdown intensified its antitumor effect. The inhibition of the MT1 receptor resulted in a substantial reduction in the migratory and invasive capacities of the cells, suggesting its potential as a therapeutic target for the treatment of ovarian cancer.
卵巢癌是一种侵袭性很强的疾病，常在晚期被诊断出来。褪黑素具有多种抗肿瘤特性，在癌症治疗中具有很大潜力。在此，我们研究了褪黑素对人卵巢癌细胞系SKOV - 3细胞凋亡、细胞迁移和激酶水平的影响，并确定这些影响是否由MT1受体的激活介导。
根据MT1受体的存在情况，将SKOV - 3细胞暴露于不同浓度的褪黑素中，我们还对褪黑素受体基因MTNR1A进行了特异性沉默。
我们的研究结果显示，MTT法表明褪黑素降低了细胞活力，流式细胞术分析显示所有褪黑素处理的细胞凋亡和坏死率增加。褪黑素显著降低了细胞的迁移和侵袭能力。碘化丙啶标记表明，褪黑素通过降低SKOV - 3细胞S期和G2/M期的DNA含量诱导细胞周期停滞。此外，参与细胞存活、增殖、运动和应激反应的AKT、ERK1/2、JNK、CREB、p70S6K、STAT3/5和p38 MAP激酶水平被褪黑素降低，MT1基因敲低后进一步降低。这些分子被发现与卵巢癌患者较低的总生存率相关。
褪黑素对卵巢癌细胞具有明显的抑癌作用，MT1受体敲低增强了其抗肿瘤作用。MT1受体的抑制导致细胞迁移和侵袭能力大幅降低，表明其作为卵巢癌治疗靶点的潜力。
