Implications of GPIIB-IIIA Integrin and Liver X Receptor in Platelet-Induced Compression of Ovarian Cancer...

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.