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. 2021 Dec 9;26(1):51.
doi: 10.1186/s11658-021-00296-3.

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

Meng Tian #  1 , Yingjie Tang #  2 , Ting Huang #  2 , Yang Liu  3 , Yingzheng Pan  4
Affiliations

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

Meng Tian et al. Cell Mol Biol Lett. .

Abstract

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.

Keywords: Acacetin; Cell invasion; Cell proliferation; Ovarian cancer; PI3K/AKT; Peritoneal mesothelial cells.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Acacetin restrained ovarian cancer cell malignancy. A Chemical structure of acacetin. B Normal human ovarian surface epithelial cell line IOSE80 was treated with the indicated doses of acacetin for 24 h; cell viability was then analyzed. C Human SKOV3 ovarian cancer cells were treated with various doses of acacetin (1–20 µM) for 24 and 48 h. Then, cell viability was determined by MTT assay. D After treatment with the indicated dose for 48 h, annexin V-FITC/PI staining was carried out to evaluate cell apoptosis. E Cell invasion was assessed by Transwell assay. *P < 0.05 vs. control group
Fig. 2
Fig. 2
Administration with acacetin offset conditioned medium-induced ovarian cancer cell growth and invasion. A Ovarian cancer cells were incubated with conditioned medium (CM) from peritoneal mesothelial cells in presence of the indicated doses of acacetin. Approximately 48 h later, cell viability was detected by MTT assay. B The protein expression of proliferation-related PCNA was analyzed by western blotting. C, D Transwell assay was performed to evaluate cell invasion. E, F The corresponding effects on protein expression of MMP-2 and MMP-9. *P < 0.05
Fig. 3
Fig. 3
Acacetin antagonized mesothelial cell-evoked inflammatory cytokine production. A Ovarian cancer cells were treated with conditioned medium from mesothelial cells under acacetin condition (10 µM). Then, the mRNA levels of IL-6 were analyzed in ovarian cancer cells by qRT-PCR. B The production of IL-6 in ovarian cancer cells was quantified by ELISA assay. C, D The subsequent effects on IL-8 mRNA and release were measured. *P < 0.05 vs. control group, #P < 0.05 vs. CM-treated group
Fig. 4
Fig. 4
Acacetin inhibits LPA release from mesothelial cells and subsequent activation of RAGE-PI3K/AKT signaling. A The contents of LPA in conditioned medium (CM) from mesothelial cells were quantified. B After incubation with CM under acacetin condition, the protein expression of RAGE, p-PI3K, p-AKT was analyzed. C–F The corresponding quantified analysis of binding bands. *P < 0.05 vs. control group, #P < 0.05 vs. CM-treated group
Fig. 5
Fig. 5
The LPA release-activated RAGE-PI3K/AKT signaling was responsible for mesothelial cell-mediated malignancy in ovarian cancer cells. A, B Following treatment with exogenous LPA, the activation of RAGE-PI3K/AKT signaling was determined in ovarian cancer cells under CM and acacetin conditions. Quantification of the above bands was analyzed by Image J software. C–F The subsequent effects on cell proliferation (C), invasion (D), the transcripts (E) and production (F) of IL-6 and IL-8were further determined. *P < 0.05 vs. control group, #P < 0.05 vs. CM-treated group, &P < 0.05 vs. CM-Aca group
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