Progesterone and calcitriol attenuate inflammatory cytokines CXCL1 and CXCL2 in ovarian and endometrial cancer cells

Cytokines/chemokines are key players in cancer-related inflammation. Increasing evidence suggests that chemokines produced by tumor cells are the mediators of metastasis. Thus, agents that can downregulate chemokines expression have potential against cancer metastasis. We have previously shown inhibition of ovarian and endometrial cancer cell growth with progesterone and calcitriol. In the present study, we evaluated the effect of these two agents on the expression of inflammatory genes. Using a RT-PCR array of inflammatory cytokines/chemokines and their receptors, we found a marked attenuation of CXCL1 and CXCL2 (GRO-a and -beta) in cancer cells by both treatments. Knockdown of NF?B resulted in a reduced expression of CXCL1 and CXCL2 and the inhibitory effect of progesterone and calcitriol on the expression of chemokines was abrogated in NF?B-silenced cancer cells. Silencing of I?Ba increased the expression of CXCL1 and CXCL2 in cancer cells, which can be attributed to the increased activation of NF?B-p65, caused by the lack of its inhibitor. Progesterone and calcitriol-induced inhibition was abolished in I?Ba-knockdown cells. Our results demonstrate that suppression of I?Ba phosphorylation by progesterone and calcitriol contributes to the reduced expression of CXCL1 and CXCL2. Downregulation of CXCL1 and CXCL2 was associated with a marked inhibition of metastasis-promoting genes. Overall, our results indicate that progesterone and calcitriol inhibit I?Ba phosphorylation, NF?B activation, and the expression of NF?B regulated metastasis promoting genes. These results provide attractive data for the possible use of progesterone and calcitriol in the management of endometrial and ovarian tumors. J. Cell. Biochem. 113: 31433152, 2012. (c) 2012 Wiley Periodicals, Inc.