Abstract 4783: Suppression of IL-6-induced metastatic potential by inhibition of mitochondrial fission in ovarian cancer cells

Abstract

Abstract Ovarian cancer is the fifth most common cause of cancer death among females in the United States. In tumor microenvironment, inflammation has been shown to play a key role, governing malignant properties of cancer cells such as angiogenesis, chemoresistance and metastasis. Interleukin-6 (IL-6) is a pro-inflammatory cytokine, produced in response to injury, infection, and inflammation. IL-6 can regulate growth, differentiation and gene expression of cells. In our previous study, we have shown that IL-6 was found to be present at a high level in malignant ascites when compared to those in benign ascites. Similar to many other oncogenic cytokines, IL-6 has been reported to increase malignant properties of cancer such as metastasis. Mitochondria, energy plants of cells regulating metabolic homeostasis, are structurally dynamic organelles undergoing continuous fission and fusion. In metastatic cancer cells, mitochondrial fission has been shown to be more frequent, than in the primary cancer cells. A key facilitator of mitochondrial fission is a molecule called dynamin-1-related protein 1 (Drp1) and its phosphorylation status can determine the activity of the molecule. Herein, we investigated the effect of the inflammatory cytokine IL-6 on the mitochondrial dynamics and the relationship between the changes in mitochondrial dynamics and metastatic potential of ovarian cancer cells. Treatment of IL-6 on epithelial ovarian cancer (EOC) cell lines (PA-1 and SKOV3) increased the metastatic potential, such as invasion and migration, verified by trans-well invasion and wound healing assays. IL-6 did not change the Drp1 expression at the protein level but modulated the ratio of phospho-Drp1s616 (active form) and phospho-Drp1s637 (inactive form), together with increased fission of mitochondria in the EOC cells. An increase of mitochondrial fission by IL-6 was confirmed through MitoSpy staining. Inhibition of mitochondrial fission by RNAi and a pharmacologic inhibitor attenuated metastatic potential of the EOC cells. Altogether, our study strongly suggests the role of mitochondrial fission in the metastatic potential of EOC cells induced by IL-6. The inhibition of mitochondrial fission could be a potential therapeutic approach suppressing the metastasis of EOC. Citation Format: Juwon Lee, Youngjin Han, Yong Sang Song. Suppression of IL-6-induced metastatic potential by inhibition of mitochondrial fission in ovarian cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4783.