Anti-Tumoral Effect of Chemerin on Ovarian Cancer Cell Lines Mediated by Activation of Interferon Alpha Response

SIMPLE SUMMARY: Chemerin is a multifunctional protein with an important role in the immune system. Recent evidence showed that chemerin also regulates the development of cancer. Ovarian cancer is a common type of tumor in women. In this study, we observed that chemerin decreases the growth of ovarian cancer cell lines in vitro when cultivated in standard cell culture or in globular multicellular aggregates. When we examined the mechanisms involved in this process, we found that treatment of ovarian cancer cells with chemerin led to the activation of genes that are known to mediate the effects of interferon alpha (IFNα). The main effect of IFNα is to defend body cells against viral infections, but it is also able to defeat cancer cells. We observed that this activation of IFNα response by chemerin resulted from the increased production of IFNα protein in ovarian cancer cells, which then reduced cancer cells numbers. However, it remains to be investigated how exactly chemerin might be able to activate interferon alpha and its anti-tumoral actions. ABSTRACT: The pleiotropic adipokine chemerin affects tumor growth primarily as anti-tumoral chemoattractant inducing immunocyte recruitment. However, little is known about its effect on ovarian adenocarcinoma. In this study, we examined chemerin actions on ovarian cancer cell lines in vitro and intended to elucidate involved cell signaling mechanisms. Employing three ovarian cancer cell lines, we observed differentially pronounced effects of this adipokine. Treatment with chemerin (huChem-157) significantly reduced OVCAR-3 cell numbers (by 40.8% on day 6) and decreased the colony and spheroid growth of these cells by half. The spheroid size of SK-OV-3 ovarian cancer cells was also significantly reduced upon treatment. Transcriptome analyses of chemerin-treated cells revealed the most notably induced genes to be interferon alpha (IFNα)-response genes like IFI27, OAS1 and IFIT1 and their upstream regulator IRF9 in all cell lines tested. Finally, we found this adipokine to elevate IFNα levels about fourfold in culture medium of the employed cell lines. In conclusion, our data for the first time demonstrate IFNα as a mediator of chemerin action in vitro. The observed anti-tumoral effect of chemerin on ovarian cancer cells in vitro was mediated by the notable activation of IFNα response genes, resulting from the chemerin-triggered increase of secreted levels of this cytokine.