Abstract 5603: Minocycline abrogates IL-6 signaling and inhibits migration, invasion and adhesion capacity of ovarian cancer cells.

Abstract

Abstract Aims: Minocycline (7-dimethylamino-6-desoxytertracycline) has been recognized as a drug with interesting pleiotropic properties including suppression of pro-inflammatory cytokine levels. The beneficial effects of minocycline arisen from suppression of proinflammatory cytokines and in particular IL-6 have been elucidated in central nervous system. However, this drug has never been examined in cancers with aberrant IL-6 expression. Considering the key role of IL-6 and its signaling pathways in the growth and progression of ovarian cancer, we evaluated whether minocycline modulates IL-6, its receptor system and signaling pathways in ovarian cancer. Methods: Expression of IL-6 in control and minocycline-treated ovarian cancer cell lines (OVCAR-3, SKOV-3 and CAOV-3) was determined by immunocytochemistry. ELISA was used to quantify the effects of minocycline on both constitutive and IL-1β or 4-OH-estradiol stimulated IL-6 expression in these cell lines. The effects of minocycline on IL-6R expression was assessed by immunocytochemistry and western blot. Activation of STAT3 and ERK1/2, two major pathways down-stream of IL-6 were evaluated by western blotting. To further characterize the influence of minocycline against IL-6 bioactivity, the effect of the drug on the functional status of SKOV-3 cells was examined by adhesion assay and transwell migration and invasion assay. Finally, to determine the effect of minocycline on IL-6 expression in vivo, female nude mice bearing intraperitoneal OVCAR-3 tumors were treated with a single 30 mg/kg dose of minocycline administered intraperitoneally for 4 and 24 h. The IL-6 expression in plasma and tumor samples excised from these animals was evaluated by ELISA and western blot. Results: We found that minocycline was potent in suppressing both constitutive and stimulated IL-6 expression in vitro. Analysis of plasma and tumors also revealed substantial down-regulation of IL-6 in minocycline-treated mice in vivo. Moreover, minocycline blocked the expression of IL-6R and phosphorylation of STAT3 and ERK1/2 time-dependently. It was also found that minocycline-treated cells exhibit dose-dependent attenuation of cell adhesion, migration and invasion capacity. Conclusion: These results demonstrated that minocycline effectively blocks IL-6 signaling in ovarian cancer. Blockage of IL-6 signaling may provide benefits for the treatment of this deadly cancer. Citation Format: Parvin Ataie-Kachoie, David L. Morris, Mohammad H. Pourgholami. Minocycline abrogates IL-6 signaling and inhibits migration, invasion and adhesion capacity of ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5603. doi:10.1158/1538-7445.AM2013-5603