Nuclear Factor-Kappa B Activity in the Host-Tumor Microenvironment of Ovarian Cancer
Final rept. 25 Jul 2011-24 Jul 2014
VANDERBILT UNIV NASHVILLE TN
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Overcoming tumor resistance to platinum chemotherapy is critical for prolonging life in women with advanced ovarian cancer. The nuclear factor-kappaB NF- B signaling pathway is a key mediator of tumorigenesis by linking inflammatory pathways to cancer. Inhibitors of NF- B such as thymoquinone TQ potentiate the effects of cytotoxic agents, including cisplatin, in ovarian cancer cells. Equally relevant are the potential effects of NF- B inhibition in host cells such as peritoneal macrophages, thought to play pro-tumor M2-like or anti-tumor M1-like roles during ovarian cancer progression. We defined patterns of NF- B activity in i ID8 tumor cells stably expressing the NGL NF- B reporter plasmid, and ii in host cells in ID8-injected NGL reporter mice. We showed increased NF- B reporter activity in tumor cells and in host macrophages during progression, and increased markers of M2 macrophages in ascites fluid. Reducing NF- B activity in tumor cells with TQ treatment elevated expression of M1 macrophage markers, while longer-term TQ treatment lead to increased ascites, elevated NF- B signaling and elevated expression of M2 markers. Combined TQ and cisplatin treatment lead to synergistic anti-tumor effects in vitro, reduced tumor burden and apoptotic marks in tumors to a greater extent than treatment with cisplatin alone, reduced M2 and induced M1 macrophage markers, and decreased levels of known pro-tumorigenic cytokines in ascites fluid.
- Medicine and Medical Research