Background:Platelets have been shown to promote ovarian cancer; however, the mechanism is poorly understood. Previously, we demonstrated that platelets reduce the size and increase the density of multi-cellular ovarian cancer spheroids in cell cultures. The objectives of this study were to determine if platelet inhibitors could counteract these effects, and to explore the mechanisms involved.Methods:FDA-approved platelet inhibitors were screened for their abilities to alter platelet effects on ovarian cancer spheroids. Mass spectrometry was used to identify proteins significantly altered in cancer cells upon exposure to platelets. The effects of platelets and/or liver x receptor agonists or antagonists on LXR activity were measured using ES-2 ovarian cancer cells transduced with an LXR-reporter vector.Results:Eptifibatide, a GPIIB-IIIA integrin inhibitor, and dipyridamole, an adenosine reuptake inhibitor, reduced and enhanced platelet effects on ovarian cancer spheroids, respectively. Proteomic studies identified the LXR/RXR and integrin pathways as mediators of platelet effects on ovarian cancer, and downstream effectors of eptifibatide.Conclusions:Integrin pathways and their downstream LXR/RXR effectors are implicated in how platelets alter ovarian cancer spheroid morphology. These results support studying eptifibatide and LXR/RXR agonists as candidate drugs for repurposing as therapeutic strategies to counteract platelet promotion of ovarian cancer.
背景：已有研究表明血小板可促进卵巢癌进展，但其机制尚不明确。我们前期研究发现，在细胞培养体系中血小板能够缩小多细胞卵巢癌球体尺寸并增加其密度。本研究旨在探究血小板抑制剂能否逆转上述效应，并探索其潜在作用机制。 方法：本研究筛选了美国食品药品监督管理局批准的血小板抑制剂，评估其改变血小板对卵巢癌球体作用的能力。采用质谱分析技术鉴定癌细胞接触血小板后发生显著变化的蛋白质。通过转导LXR报告载体的ES-2卵巢癌细胞系，检测血小板和/或肝X受体激动剂或拮抗剂对LXR活性的影响。 结果：GPIIB-IIIA整合素抑制剂依替巴肽可减弱血小板对卵巢癌球体的作用，而腺苷再摄取抑制剂双嘧达莫则增强该效应。蛋白质组学研究证实LXR/RXR通路与整合素通路是血小板影响卵巢癌的介质，也是依替巴肽的下游效应器。 结论：整合素通路及其下游LXR/RXR效应器参与调控血小板改变卵巢癌球体形态的过程。这些结果为研究依替巴肽及LXR/RXR激动剂作为候选药物提供了依据，支持将其重新定位为抑制血小板促进卵巢癌作用的治疗策略。
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