Abstract
Abstract Chronic inflammation has been shown to play a critical role in growth of cancers. NF-κB is a transcriptional factor that regulates diverse biological processes, including cell proliferation, survival and inflammation. We have previously shown inhibition of endometrial and ovarian cancer cell growth with progesterone and calcitriol. In the present study, we evaluated the effect of progesterone and calcitriol on the expression of inflammatory genes. Using RT-PCR array of inflammatory cytokine and receptor genes, we found two inflammatory cytokines, CXCL1 and -2 (GRO-A and -B), downregulated by both treatments. PCR array results were validated by Western blotting. Knockdown of NF-kB resulted in a reduced expression of CXCL1 and -2 and the inhibitory effect of progesterone and calcitriol on the expression of cytokines was abrogated in NF-kB-silenced cancer cells. Silencing of IkBα increased the expression of CXCL1 and -2 in cancer cells, which can be attributed to the increased activation of NF-kB-p65, caused by the lack of its inhibitor. Progesterone and calcitriol-induced inhibition was abolished in IkBα-knockdown cells. Our results demonstrate that suppression of IkBα phosphorylation by progesterone and calcitriol contributes to the reduced expression of CXCL1 and -2. We investigated the effect of CXCL1 and -2 downregulation on metastasis-promoting genes and found a marked inhibition of CXCR4, COX2 and matrix metalloproteinases (MMP2 and MPP-9). Overall, our results indicate that progesterone and calcitriol downregulate NF-kB in cancer cells, leading to the suppression of metastasis, thus providing the molecular basis for the treatment of endometrial and ovarian cancer patients with progesterone and calcitriol. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1412. doi:1538-7445.AM2012-1412
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