FKA‐A NPs enhances PTX‐A NPs efficacy to suppress ovarian cancer via regulating Skp2/YAP pathway

摘要

Abstract Recurrence and distant metastasis after paclitaxel (PTX)‐based chemotherapy in ovarian cancer (OC) patients remains a clinical obstacle. Flavokawain A (FKA) is a novel chalcone from kava plant that can induce G2/M arrest and inhibit invasion and metastasis in different tumor cells. In this study, we examined the effects and the molecular mechanism of sodium aescinate (Aes)‐stabilized nanoparticles FKA‐A NPs in enhancing the efficacy of PTX‐A NPs in vitro and in vivo. We showed that FKA‐A NPs combined with PTX‐A NPs notably inhibited the proliferation and migration and reduced the expression of EMT‐related markers in OCs. YAP nuclear translocation and its downstream signaling pathway were remarkably activated after PTX‐A NPs treatment in OCs. FKA‐A NPs obviously inhibited YAP nuclear translocation and reduced the transcriptional activity of YAP target genes. Simultaneously, FKA‐A NPs dose and time dependently inhibited Skp2 expression in A2780 and Skov3 cells. In contrast, overexpression of Skp2 significantly attenuated the inhibition of FKA‐A NPs on YAP nuclear translocation. In OC homograft mice, treatment with FKA‐A NPs and PTX‐A NPs significantly suppressed the growth of homograft tumor compared with PTX‐A NPs but did not decrease mice's body weight. In summary, we demonstrate that FKA‐A NPs enhance the efficacy of PTX‐A NPs against OCs in vitro and in vivo via reducing Skp2 expression, thus suppressing YAP nuclear translocation and activity of its target genes.