Amelioration of human peritoneal mesothelial cell co-culture-evoked malignant potential of ovarian cancer cells by acacetin involves LPA release-activated RAGE-PI3K/AKT signaling

BACKGROUND: Ovarian cancer is a devastating gynecological malignancy and frequently presents as an advanced carcinoma with disseminated peritoneum metastasis. Acacetin exerts anti-cancerous effects in several carcinomas. Here, we sought to investigate acacetin function in ovarian cancer malignancy triggered by peritoneal mesothelial cells. METHODS: Peritoneal mesothelial cells were treated with acacetin, and then the conditioned medium was collected to treat ovarian cancer cells. Then, cell proliferation was analyzed by MTT assay. Transwell analysis was conducted to evaluate cell invasion. Protein expression was determined by western blotting. ELISA and qRT-PCR were applied to analyze inflammatory cytokine levels. The underlying mechanism was also explored. RESULTS: Acacetin suppressed cell proliferation and invasion, but enhanced cell apoptosis. Furthermore, mesothelial cell-evoked malignant characteristics were inhibited when mesothelial cells were pre-treated with acacetin via restraining cell proliferation and invasion, concomitant with decreases in proliferation-related PCNA, MMP-2 and MMP-9 levels. Simultaneously, acacetin reduced mesothelial cell-induced transcripts and production of pro-inflammatory cytokine IL-6 and IL-8 in ovarian cancer cells. Mechanically, acacetin decreased lysophosphatidic acid (LPA) release from mesothelial cells, and subsequent activation of receptor for advanced glycation end-products (RAGE)-PI3K/AKT signaling in ovarian cancer cells. Notably, exogenous LPA restored the above pathway, and offset the efficacy of acacetin against mesothelial cell-evoked malignancy in ovarian cancer cells, including cell proliferation, invasion and inflammatory cytokine production. CONCLUSIONS: Acacetin may not only engender direct inhibition of ovarian cancer cell malignancy, but also antagonize mesothelial cell-evoked malignancy by blocking LPA release-activated RAGE-PI3K/AKT signaling. Thus, these findings provide supporting evidence for a promising therapeutic agent against ovarian cancer. GRAPHICAL ABSTRACT: [Image: see text]